Antagonists of the muscarinic acetylcholine receptor m4

ABSTRACT

Disclosed herein are octahydropyrrolo[3,4-b]pyrrole compounds, which may be useful as antagonists of the muscarinic acetylcholine receptor M4 (mAChR M4). Also disclosed herein are methods of making the compounds, pharmaceutical compositions comprising the compounds, and methods of treating disorders using the compounds and compositions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.62/542,567, filed Aug. 8, 2017, which is hereby incorporated byreference in its entirety.

TECHNICAL FIELD

The present disclosure relates to compounds, compositions, and methodsfor treating disorders associated with muscarinic acetylcholine receptordysfunction.

BACKGROUND

Parkinson's disease (PD) is the second most common neurodegenerativedisease with an increasing prevalence as a function of age. Moreover,early-onset PD is also increasing. A hallmark of PD is the progressivedegeneration and loss of dopaminergic neurons in the substantia nigra(SN) and basal ganglia (BG), leading to pronounced motor symptomsincluding bradykinesia, tremor, rigidity, gait dysfunction and posturalinstability. At present, levodopa (L-DOPA) is the standard of care fortreating the motor symptoms, but it is not curative, and prolonged usecan engender L-DOPA induced dyskinesia (LID).

Prior to L-DOPA, compounds with anticholinergic activity represented thepreferred mode of PD treatment. Cholinergic neurons provide importantneuromodulatory control of the BG motor circuit. While the actions ofcholinergic pathways on basal ganglia pathways are complex, activationof muscarinic acetylcholine receptors (mAChRs) generally have actionsthat oppose dopamine (DA) signaling. For instance, mAChR agonistsinhibit DA release, and inhibit multiple behavioral effects of drugsthat increase DA levels and signaling. Interestingly, muscarinicacetylcholine receptor (mAChR) antagonists were the first availabletreatments for PD and are still widely used for treatment of thisdisorder. While many studies of the actions of mAChR antagonists werecarried out before randomized controlled trials were introduced, recentwell controlled double-blind cross-over design studies demonstratesignificant improvement in multiple aspects of motor function inpatients receiving mAChR antagonists. Unfortunately, mAChR antagonistshave a number of dose-limiting adverse effects that severely limit theirclinical utility, including multiple peripheral adverse effects, as wellas confusion and severe cognitive disturbances.

Because adverse effects associated with mAChR antagonists limit thedoses that can be tolerated, previous clinical studies may underestimatethe efficacy that could be achieved if doses of mAChR antagonists couldbe increased to achieve more complete blockade of specific mAChRsubtypes responsible for the antiparkinsonian effects of these agents.The mAChRs include five subtypes, termed M₁-M₅. Available mAChRantagonists, such as scopolamine, are nonselective across thesesubtypes, and many of their adverse effects are likely mediated by mAChRsubtypes that are not involved in the antiparkinsonian activity. Thus,compounds possessing a more selective profile for individual mAChRs mayoffer an advantage in PD, as well as related disorders such as dystonia.For example, some studies indicate that the M₄ mAChR subtype may play adominant role in mAChR regulation of basal ganglia motor function.

SUMMARY

In one aspect, disclosed are compounds of formula (I),

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   A is a five- or six-membered heteroarylene having 1, 2 or 3        heteroatoms independently selected from N, O and S;

R¹ is selected from hydrogen, halo, —OR^(a), —NR^(b)R^(c), aryl, andheteroaryl;

-   -   R² is selected from hydrogen, C₁-C₄ alkyl, halo, and —OR^(d);    -   R³ is selected from hydrogen and C₁-C₄ alkyl;    -   R⁴ is selected from C₁-C₈ alkyl, C₁-C₈ alkenyl, and        —(CR^(e)R^(f))_(n)—Y′;    -   each Y′ is independently selected from cycloalkyl, cycloalkenyl,        heterocycle, aryl, and heteroaryl;    -   each R^(a), R^(b), R^(c), and R^(d) is independently selected        from hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, and aryl;    -   each R^(e) is independently selected from hydrogen and C₁-C₄        alkyl;    -   each R^(f) is independently selected from hydrogen, C₁-C₄ alkyl,        and aryl; and    -   n is 0, 1, 2, 3, or 4;    -   wherein each aryl, heteroaryl, cycloalkyl, cycloalkenyl, and        heterocycle is independently unsubstituted or substituted with        1, 2, or 3 substituents independently selected from C₁-C₄ alkyl,        halo, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄        hydroxyalkyl, hydroxy, cyano, and benzyl.

Also disclosed are pharmaceutical compositions comprising the compounds,methods of making the compounds, kits comprising the compounds, andmethods of using the compounds, compositions and kits for treatment ofdisorders, such as neurological and/or psychiatric disorders, associatedwith muscarinic acetylcholine receptor dysfunction in a mammal.

DETAILED DESCRIPTION

Disclosed herein are compounds that are antagonists of the muscarinicacetylcholine receptor M₄ (mAChR M₄), methods of making the compounds,pharmaceutical compositions comprising the compounds, and methods oftreating disorders using the compounds and pharmaceutical compositions.The compounds include substituted octahydropyrrolo[3,4-b]pyrrolecompounds.

1. Definitions

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art. In case of conflict, the present document, includingdefinitions, will control. Preferred methods and materials are describedbelow, although methods and materials similar or equivalent to thosedescribed herein can be used in practice or testing of the presentinvention. All publications, patent applications, patents and otherreferences mentioned herein are incorporated by reference in theirentirety. The materials, methods, and examples disclosed herein areillustrative only and not intended to be limiting.

The terms “comprise(s),” “include(s),” “having,” “has,” “can,”“contain(s),” and variants thereof, as used herein, are intended to beopen-ended transitional phrases, terms, or words that do not precludethe possibility of additional acts or structures. The singular forms“a,” “an” and “the” include plural references unless the context clearlydictates otherwise. The present disclosure also contemplates otherembodiments “comprising,” “consisting of” and “consisting essentiallyof,” the embodiments or elements presented herein, whether explicitlyset forth or not.

The modifier “about” used in connection with a quantity is inclusive ofthe stated value and has the meaning dictated by the context (forexample, it includes at least the degree of error associated with themeasurement of the particular quantity). The modifier “about” shouldalso be considered as disclosing the range defined by the absolutevalues of the two endpoints. For example, the expression “from about 2to about 4” also discloses the range “from 2 to 4.” The term “about” mayrefer to plus or minus 10% of the indicated number. For example, “about10%” may indicate a range of 9% to 11%, and “about 1” may mean from0.9-1.1. Other meanings of “about” may be apparent from the context,such as rounding off, so, for example “about 1” may also mean from 0.5to 1.4.

Definitions of specific functional groups and chemical terms aredescribed in more detail below. For purposes of this disclosure, thechemical elements are identified in accordance with the Periodic Tableof the Elements, CAS version, Handbook of Chemistry and Physics, 75^(th)Ed., inside cover, and specific functional groups are generally definedas described therein. Additionally, general principles of organicchemistry, as well as specific functional moieties and reactivity, aredescribed in Organic Chemistry, Thomas Sorrell, University ScienceBooks, Sausalito, 1999; Smith and March March's Advanced OrganicChemisty, 5^(th) Edition, John Wiley & Sons. Inc., New York, 2001;Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., NewYork, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3^(rd)Edition, Cambridge University Press, Cambridge, 1987; the entirecontents of each of which are incorporated herein by reference.

The term “alkoxy,” as used herein, refers to an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy and tert-butoxy.

The term “alkyl,” as used herein, means a straight or branched,saturated hydrocarbon chain containing from 1 to 10 carbon atoms. Theterm “lower alkyl” or “C₁-C₆-alkyl” means a straight or branched chainhydrocarbon containing from 1 to 6 carbon atoms. The term “C₁-C₃-alkyl”means a straight or branched chain hydrocarbon containing from 1 to 3carbon atoms. Representative examples of alkyl include, but are notlimited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl,3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl,4,4-dimethylpentan-2-yl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

The term “alkenyl,” as used herein, means a straight or branched,hydrocarbon chain containing at least one carbon-carbon double bond andfrom 2 to 10 carbon atoms.

The term “alkoxyalkyl,” as used herein, refers to an alkoxy group, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein.

The term “alkoxyfluoroalkyl,” as used herein, refers to an alkoxy group,as defined herein, appended to the parent molecular moiety through afluoroalkyl group, as defined herein.

The term “alkylene,” as used herein, refers to a divalent group derivedfrom a straight or branched chain hydrocarbon of 1 to 10 carbon atoms,for example, of 2 to 5 carbon atoms. Representative examples of alkyleneinclude, but are not limited to, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂—,—CH₂CH₂CH₂CH₂—, —CH₂CH(CH₃)CH₂CH₂—, and —CH₂CH₂CH₂CH₂CH₂—.

The term “alkylamino,” as used herein, means at least one alkyl group,as defined herein, is appended to the parent molecular moiety through anamino group, as defined herein.

The term “amide,” as used herein, means —C(O)NR— or —NRC(O)—, wherein Rmay be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle,alkenyl, or heteroalkyl.

The term “aminoalkyl,” as used herein, means at least one amino group,as defined herein, is appended to the parent molecular moiety through analkylene group, as defined herein.

The term “amino,” as used herein, means —NR_(x)R_(y), wherein R_(x) andR_(y) may be hydrogen, alkyl, cycloalkyl, aryl, heterokuyl, heterocycle,alkenyl, or heteroalkyl. In the case of an aminoalkyl group or any othermoiety where amino appends together two other moieties, amino may bewherein —NR_(x)—, wherein R_(x) may be hydrogen, alkyl, cycloalkyl,aryl, heteroaryl, heterocycle, alkenyl, or heteroalkyl.

The term “aryl,” as used herein, refers to a phenyl group, or a bicyclicfused ring system. Bicyclic fused ring systems are exemplified by aphenyl group appended to the parent molecular moiety and fused to acycloalkyl group, as defined herein, a phenyl group, a heteroaryl group,as defined herein, or a heterocycle, as defined herein. Representativeexamples of aryl include, but are not limited to, indolyl, naphthyl,phenyl, benzodioxolyl, and tetrahydroquinolinyl.

The term “cyanoalkyl,” as used herein, means at least one —CN group, isappended to the parent molecular moiety through an alkylene group, asdefined herein.

The term “cyanofluoroalkyl,” as used herein, means at least one —CNgroup, is appended to the parent molecular moiety through a fluoroalkylgroup, as defined herein.

The term “cycloalkoxy,” as used herein, refers to a cycloalkyl group, asdefined herein, appended to the parent molecular moiety through anoxygen atom.

The term “cycloalkyl,” as used herein, refers to a carbocyclic ringsystem containing three to ten carbon atoms, zero heteroatoms and zerodouble bonds. The cycloalkyl may be monocyclic, bicyclic, bridged,fused, or spirocyclic. Representative examples of cycloalkyl include,but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl,and bicyclo[1.1.1]pentanyl. “Cycloalkyl” also includes carbocyclic ringsystems in which a cycloalkyl group is appended to the parent molecularmoiety and is fused to an aryl group as defined herein (e.g., a phenylgroup), a heteroaryl group as defined herein, or a heterocycle asdefined herein. Representative examples of such cycloalkyl groupsinclude, but are not limited to, 2,3-dihydro-1H-indenyl (e.g.,2,3-dihydro-1H-inden-1-yl and 2,3-dihydro-1H-inden-2-yl),6,7-dihydro-5H-cyclopenta[b]pyridinyl (e.g.,6,7-dihydro-5H-cyclopenta[b]pyridin-6-yl), oxaspiro[3.3]heptanyl (e.g.,2-oxaspiro[3.3]heptan-6-yl), and 5,6,7,8-tetrahydroquinolinyl5,6,7,8-tetrahydroquinolin-5-yl).

The term “cycloalkenyl,” as used herein, means a non-aromatic monocyclicor multicyclic ring system containing at leak one carbon-carbon doublebond and preferably having from 5-10 carbon atoms per ring. ExemplaryInonocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl,cycloheptenyl, and bicyclo[2.2.1]heptenyl (e.g.,bicyclo[2.2.1]hept-5-en-2-yl).

The term “fluoroalkyl,” as used herein, means an alkyl group, as definedherein, in which one, two, three, four, five, six, seven or eighthydrogen atoms are replaced by fluorine. Representative examples offluoroalkyl include, but are not limited to, 2-fluoroethyl,2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl,and trifluoropropyl such as 3,3,3-trifluoropropyl.

The term “fluoroalkoxy,” as used herein, means at least one fluoroalkylgroup, as defined herein, is appended to the parent molecular moietythrough an oxygen atom. Representative examples of fluoroalkoxy include,but are not limited to, difluoromethoxy, trifluoromethoxy and2,2,2-trifluoroethoxy.

The term “halogen” or “halo,” as used herein, means Cl, Br, I, or F.

The term “haloalkyl,” as used herein, means an alkyl group, as definedherein, in which one, two, three, four, five, six, seven or eighthydrogen atoms are replaced by a halogen.

The term “haloalkoxy,” as used herein, means at least one haloalkylgroup, as defined herein, is appended to the parent molecular moietythrough an oxygen atom.

The term “halocycloalkyl,” as used herein, means a cycloalkyl group, asdefined herein, in which one or more hydrogen atoms are replaced by ahalogen.

The term “heteroalkyl,” as used herein, means an alkyl group, as definedherein, in which one or more of the carbon atoms has been replaced by aheteroatom selected from S, O, P and N. Representative examples ofheteroalkyls include, but are not limited to, alkyl ethers, secondaryand tertiary alkyl amines, amides, and alkyl sulfides.

The term “heteroaryl,” as used herein, refers to an aromatic monocyclicring or an aromatic bicyclic ring system. The aromatic monocyclic ringsare five or six membered rings containing at least one heteroatomindependently selected from the group consisting of N, O and S (e.g. 1,2, 3, or 4 heteroatoms independently selected from O, S, and N). Thefive membered aromatic monocyclic rings have two double bonds and thesix membered six membered aromatic monocyclic rings have three doublebonds. The bicyclic heteroaryl groups are exemplified by a monocyclicheteroaryl ring appended to the parent molecular moiety and fused to amonocyclic cycloalkyl group, as defined herein, a monocyclic aryl group,as defined herein, a monocyclic heteroaryl group, as defined herein, ora monocyclic heterocycle, as defined herein. Representative examples ofheteroaryl include, but are not limited to, indolyl, pyridinyl(including pyridin-2-yl, pyridin-3-yl, pyridin-4-yl), pyrimidinyl,pyrazinyl, pyridazinyl, pyrazolyl, pyrrolyl, benzopyrazolyl,1,2,3-triazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl,1,3,4-oxadiazolyl, thiazolyl, isothiazolyl, thienyl, benzimidazolyl,benzothiazotyl, benzoxazolyl, benzoxadiazolyl, benzothienyl,benzofuranyl, isobenzofuranyl, furanyl, oxazolyl, isoxazolyl, purinyl,isoindolyl, quinoxalinyl, indazolyl, quinazolinyl, 1,2,4-triazinyl,1,3,5-triazinyl, isoquinolinyl, quinolinyl,6,7-dihydro-1,3-benzothiazolyl, imidazo[1,2-a]pyridinyl, naphthyridinyl,pyridoimidazolyl, thiazolo[5,4-b]pyridin-2-yl,thiazolo[5,4-d]pyrimidin-2-yl.

The term “heterocycle” or “heterocyclic,” as used herein, means amonocyclic heterocycle, a bicyclic heterocycle, or a tricyclicheterocycle. The monocyclic heterocycle is a three-, four-, five-, six-,seven-, or eight-membered ring containing at least one heteroatomindependently selected from the group consisting of O, N, and S. Thethree- or four-membered ring contains zero or one double bond, and oneheteroatom selected from the group consisting of O, N, and S. Thefive-membered ring contains zero or one double bond and one, two orthree heteroatoms selected from the group consisting of O, N and S. Thesix-membered ring contains zero, one or two double bonds and one, two,or three heteroatoms selected from the group consisting of O, N, and S.The seven- and eight-membered rings contains zero, one, two, or threedouble bonds and one, two, or three heteroatoms selected from the groupconsisting of O, N, and S. Representative examples of monocyclicheterocycles include, but are not limited to, azetidinyl, azepanyl,aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl,1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl,isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl,2-oxo-3-piperidinyl, 2-oxoazepan-3-yl, oxadiazolinyl, oxadiazolidinyl,oxazolinyl, oxazolidinyl, oxetanyl, oxepanyl, oxocanyl, piperazinyl,piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl,tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, 1,2-thiazinanyl,1,3-thiazinanyl, thiazolinyl, thiazolidinyl, thiomorpholinyl,1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, andtrithianyl. The bicyclic heterocycle is a monocyclic heterocycle fusedto a phenyl group, or a monocyclic heterocycle fused to a monocycliccycloalkyl, or a monocyclic heterocycle fused to a monocycliccycloalkenyl, or a monocyclic heterocycle fused to a monocyclicheterocycle, or a Spiro heterocycle group, or a bridged monocyclicheterocycle ring system in which two non-adjacent atoms of the ring arelinked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or analkenylene bridge of two, three, or four carbon atoms. Representativeexamples of bicyclic heterocycles include, but are not limited to,benzopyranyl, benzothiopyranyl, chromanyl, 2,3-dihydrobenzofuranyl,2,3-dihydrobenzothienyl, 2,3-dihydroisoquinoline,2-azaspiro[3.3]heptan-2-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl,azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl),azabicyclo[3.1.0]hexanyl (including 3-azabicyclo[3.1.0]hexan-3-yl,2,3-dihydro-1H-indolyl, isoindolinyl, octahydrocyclopenta[c]pyrrolyl,octahydropyrrolopyridinyl, and tetrahydroisoquinolinyl. Tricyclicheterocycles are exemplified by a bicyclic heterocycle fused to a phenylgroup, or a bicyclic heterocycle fused to a monocyclic cycloalkyl, or abicyclic heterocycle fused to a monocyclic cycloalkenyl, or a bicyclicheterocycle fused to a monocyclic heterocycle, or a bicyclic heterocyclein which two non-adjacent atoms of the bicyclic ring are linked by analkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridgeof two, three, or four carbon atoms. Examples of tricyclic heterocyclesinclude, but are not limited to, octahydro-2,5-epoxypentalene,hexahydro-2H-2,5-methanocyclopenta[b]furan,hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-adamantane(1-azatricyclo[3.3.1.13,7]decane), and oxa-adamantane(2-oxatricyclo[3.3.1.13,7]decane). The monocyclic, bicyclic, andtricyclic heterocycles are connected to the parent molecular moietythrough any carbon atom or any nitrogen atom contained within the rings,and can be unsubstituted or substituted.

The term “hydroxyl” or “hydroxy,” as used herein, means an —OH group.

The term “hydroxyalkyl,” as used herein, means at least one —OH group,is appended to the parent molecular moiety through an alkylene group, asdefined herein.

The term “hydroxyfluoroalkyl,” as used herein, means at least one —OHgroup, is appended to the parent molecular moiety through a fluoroalkylgroup, as defined herein.

In some instances, the number of carbon atoms in a hydrocarbylsubstituent alkyl or cycloalkyl) is indicated by the prefix“C_(x)-C_(y)-”, wherein x is the minimum and y is the maximum number ofcarbon atoms in the substituent. Thus, for example, “C₁-C₃-alkyl” refersto an alkyl substituent containing from 1 to 3 carbon atoms.

The term “sulfonamide,” as used herein, means —S(O)₂NR— or —NRS(O)—,wherein R may be hydrogen, alkyl, cycloalkyl, aryl, heteroaryl,heterocycle, alkenyl, or heteroalkyl.

The term “substituents” refers to a group “substituted” on an aryl,heteroaryl, phenyl or pyridinyl group at any atom of that group. Anyatom can be substituted.

The term “substituted” refers to a group that may be further substitutedwith one or more non-hydrogen substituent groups. Substituent groupsinclude, but are not limited to, halogen, ═O (oxo), ═S (thioxo), cyano,nitro, fluoroalkyl, alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl,alkynyl, haloalkyl, haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl,aryl, heteroaryl, heterocycle, cycloalkylalkyl, heteroarylalkyl,arylalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene,aryloxy, phenoxy, benzyloxy, amino, alkylamino, acylamino, aminoalkyl,arylamino, sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl,arylsulfonyl, aminosulfonyl, sulfinyl —COOH, ketone, amide, carbamate,and acyl. For example, if a group is described as being “optionallysubstituted” (such as an alkyl, alkenyl, alkynyl, aryl, heteroaryl,cycloalkyl, heteroalkyl, heterocycle or other group such as an R group),it may have 0, 2, 3, 4 or 5 substituents independently selected fromhalogen, ═O (oxo), ═S (thioxo), cyano, nitro, fluoroalkyl,alkoxyfluoroalkyl, fluoroalkoxy, alkyl, alkenyl, alkynyl, haloalkyl,haloalkoxy, heteroalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl,heterocycle, cycloalkylalkyl, heteroarylalkyl, arylalkyl, hydroxy,hydroxyalkyl, alkoxy, alkoxyalkyl, alkylene, aryloxy, phenoxy,benzyloxy, amino, alkylamino, acylamino, aminoalkyl, arylamino,sulfonylamino, sulfinylamino, sulfonyl, alkylsulfonyl, arylsulfonyl,aminosulfonyl, sulfinyl, —COOH, ketone, amide, carbamate, and acyl.

The term “

” designates a single bond (—) or a double bond (═).

For compounds described herein, groups and substituents thereof may beselected in accordance with permitted valence of the atoms and thesubstituents, such that the selections and substitutions result in astable compound, e.g., which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, etc.

The term “mAChR M₄ receptor antagonist” as used herein refers to anyexogenously administered compound or agent that directly or indirectlyantagonizes mAChR M₄, for example in an animal, in particular a mammal(e.g., a human).

For the recitation of numeric ranges herein, each intervening numberthere between with the same degree of precision is explicitlycontemplated. For example, for the range of 6-9, the numbers 7 and 8 arecontemplated in addition to 6 and 9, and for the range 6.0-7.0, thenumber 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 areexplicitly contemplated.

2. Compounds

In one aspect, disclosed is a compound of formula (I):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   A is a five- or six-membered heteroarylene having 1, 2 or 3        heteroatoms independently selected from N, O and S;    -   R¹ is selected from hydrogen, halo, —OR^(a), —NR^(b)R^(c), aryl,        and heteroaryl;    -   R² is selected from hydrogen, C₁-C₄ alkyl, halo, and —OR^(d);    -   R³ is selected from hydrogen and C₁-C₄ alkyl;    -   R⁴ is selected from C₁-C₈ alkyl, C₁-C₈ alkenyl, and        —(CR^(c)R^(f))_(n)—Y′;    -   each Y′ is independently selected from cycloalkyl, cycloalkenyl,        heterocycle, aryl, and heteroaryl;    -   each R^(a), R^(b), R^(c), and R^(d) is independently selected        from hydrogen, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, and aryl;    -   each R^(e) is independently selected from hydrogen and C₁-C₄        alkyl;    -   each R^(f) is independently selected from hydrogen, C₁-C₄ alkyl,        and aryl; and    -   n is 0, 1, 2, 3, or 4;    -   wherein each aryl, heteroaryl, cycloalkyl, cycloalkenyl, and        heterocycle is independently unsubstituted or substituted with        1, 2, or 3 substituents independently selected from C₁-C₄ alkyl,        halo, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, C₁-C₄        hydroxyalkyl, hydroxy, cyano, and benzyl.

In some embodiments, A is selected from:

-   -   wherein:    -   T is selected from O, S and NH;    -   U, V, W, X, Y and Z are independently selected from N and        CR^(g); and    -   each R^(g) is independently selected from hydrogen, C₁-C₄ alkyl,        halo, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy, and        hydroxy, wherein 1-3 of W, X, Y, and Z are N.

In some embodiments, A is:

-   -   wherein:    -   one or two of W, X, Y and Z is N and the other two are CR^(g);        and    -   each R^(g) is hydrogen.

In some embodiments, A is selected from:

In some embodiments, A is:

In some embodiments, R¹ is selected from aryl and heteroaryl. In someembodiments: R¹ is selected from phenyl and a 5- or 6- memberedheteroaryl having 1, 2, or 3 heteroatoms independently selected from N,O, and S; and the phenyl or heteroaryl is unsubstituted or substitutedwith 1, 2, or 3 substituents independently selected from halo and C₁-C₄alkyl. In some embodiments, R^(I) is selected from phenyl, pyridyl, andpyrazolyl, each of which is independently^(,) unsubstituted orsubstituted with 1, 2, or 3 substituents independently selected fromhalo (e.g., fluoro and chloro) and C₁-C₄ alkyl (e.g., methyl and ethyl).

In some embodiments, R² is hydrogen.

In some embodiments, R³ is hydrogen.

In some embodiments, R⁴ is selected from C₁-C₈ alkyl and C₁-C₈ alkenyl.In some embodiments, R⁴ is selected from C₄-C₆ alkyl and C₄-C₆ alkenyl.In some embodiments, R⁴ is selected from n-pentyl, hex-3-en-1-yl,neopentyl, and 3,3-dimethylbutyl.

In some embodiments, R⁴ is —(CR^(e)R^(f))_(n)—Y′. In some embodiments:R⁴ is —(CR^(e)R^(f))_(n)—Y′; R^(e) is hydrogen; each R^(f) isindependently selected from hydrogen, methyl, and phenyl; n is 0, 1, 2,or 3; Y′ is selected from: C₃-C₁₀ cycloalkyl; C₅-C₁₀ cycloalkenyl;phenyl; a 5- or 6-membered heteroaryl having 1, 2, or 3 heteroatomsindependently selected from N, O, and S; and a 5- or 6-memberedheterocycle having 1, 2, or 3 heteroatoms independently selected from N,O, and S; wherein Y′ is unsubstituted or substituted with one or twosubstituents independently selected from halo, C₁-C₄ alkyl, and benzyl.In some embodiments, Y′ is C₃-C₁₀ cycloalkyl. In some embodiments, Y′ isadamantyl. In some embodiments, n is 0 and Y′ is adamantyl. In someembodiments, Y′ is phenyl. In some embodiments, Y′ is unsubstitutedphenyl. In some embodiments: n is 0, 1, or 2; R^(e) is hydrogen; eachR^(f) is independently selected from hydrogen, methyl, and phenyl; andY′ is phenyl. In some embodiments: n is 0, 1, or 2; R^(e) is hydrogen;each R^(f) is independently selected from hydrogen, methyl, and phenyl;and Y′ is unsubstituted phenyl. In some embodiments: n is 0, 1, or 2;R^(e) and R^(f) are each hydrogen; and Y′ is unsubstituted phenyl. Insome embodiments: n is 0, 1, or 2; R^(e) and R^(f) are each hydrogen;and Y′ is phenyl. In some embodiments: n is 0, 1, or 2; R^(e) and R^(f)are each hydrogen; and Y′ is unsubstituted phenyl. In some embodiments,Y′ is C₅-C₁₀ cycloalkenyl. In some embodiments, Y′ isbicyclo[2.2.1]hept-5-en-2-yl. In some embodiments, Y′ is a 5- or6-membered heteroaryl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S. In some embodiments, Y′ is pyridyl. In someembodiments, n is 0, and Y′ is pyridyl that is unsubstituted orsubstituted with 1 substituent selected from C₁-C₄ alkyl (e.g., methyl).In some embodiments, Y′ is a 5- or 6-membered heterocycle having 1, 2,or 3 heteroatoms independently selected from N, O, and S. In someembodiments, n is 0, and Y′ is a 6-membered heterocycle having oneheteroatom selected from N and O, wherein the heterocycle isunsubstituted or substituted with one substituent that is benzyl.

In some embodiments, the compound is a compound of formula (Ia):

In some embodiments, R¹ is selected from aryl and heteroaryl. In someembodiments: R¹ is selected from phenyl and a 5- or 6-memberedheteroaryl having 1, 2, or 3 heteroatoms independently selected from N,O, and S; and the phenyl or heteroaryl is unsubstituted or substitutedwith 1, 2, or 3 substituents independently selected from halo and C₁-C₄alkyl. In some embodiments, R¹ is selected from phenyl, pyridyl, andpyrazolyl, each of which is independently unsubstituted or substitutedwith 1, 2, or 3 substituents independently selected from halo (e.g.,fluoro and chloro) and C₁-C₄ alkyl (e.g., methyl and ethyl).

In some embodiments, R⁴ is —(CR^(e)R^(f))_(n)—Y′. In some embodiments:R⁴ is —(CR^(e)R^(f))_(n)—Y′; R^(e) is hydrogen; each R^(f) isindependently selected from hydrogen, methyl, and phenyl; n is 0, 1, 2,or 3; Y′ is selected from: C₃-C₁₀ cycloalkyl; C₅-C₁₀ cycloalkenyl;phenyl; a 5- or 6-membered heteroaryl having 1, 2, or 3 heteroatomsindependently selected from N, O, and S; and a 5- or 6-memberedheterocycle having 1, 2, or 3 heteroatoms independently selected from N,O, and S; wherein Y′ is unsubstituted or substituted with one or twosubstituents independently selected from halo, C₁-C₄ alkyl, and benzyl.In some embodiments, Y′ is C₃-C₁₀ cycloalkyl. In some embodiments, Y′ isadamantyl. In some embodiments, n is 0 and Y′ is adamantyl. In someembodiments, Y′ is phenyl. In some embodiments, Y′ is unsubstitutedphenyl. In some embodiments: n is 0, 1, or 2; R^(e) is hydrogen; eachR^(f) is independently selected from hydrogen, methyl, and phenyl; andY′ is phenyl. In some embodiments: n is 0, 1, or 2; R^(e) is hydrogen;each R^(f) is independently selected from hydrogen, methyl, and phenyl;and Y′ is unsubstituted phenyl. In some embodiments: n is 0, 1, or 2;R^(e) and R^(f) are each hydrogen; and Y′ is unsubstituted phenyl. Insome embodiments: n is 0, 1, or 2; R^(e) and R^(f) are each hydrogen;and Y′ is phenyl. In some embodiments: n is 0, 1, or 2; R^(c) and R^(f)are each hydrogen; and Y′ is unsubstituted phenyl. In some embodiments,Y′ is C₅-C₁₀ cycloalkenyl. In some embodiments, Y′ isbicyclo[2.2.1]hept-5-en-2-yl. In some embodiments, Y′ is a 5- or6-membered heteroaryl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S. In some embodiments, Y′ is pyridyl. In someembodiments, n is 0, and Y′ is pyridyl that is unsubstituted orsubstituted with 1 substituent selected from C₁-C₄ alkyl (e.g., methyl).In some embodiments, Y′ is a 5- or 6-membered heterocycle having 1, 2,or 3 heteroatoms independently selected from N, O, and S. In someembodiments, n is 0, and Y′ is a 6-membered heterocycle having oneheteroatom selected from N and O, wherein the heterocycle isunsubstituted or substituted with one substituent that is benzyl.

Representative compounds of formula (I) include, but are not limited to:

-   -   5-(adamantan-1-ylmethyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole;    -   1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-(4,4-dimethylpentyl)octahydropyrrolo[3,4-b]pyrrole;    -   5-(bicyclo[2.2.1]hept-5-en-2-ylmethyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole;    -   1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-((3-methylpyridin-2-yl)methyl)octahydropyrrolo[3,4-b]pyrrole;    -   5-benzyl-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole;    -   1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-phenethyloctahydropyrrolo[3,4-b]pyrrole;    -   1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-(3-phenylpropyl)octahydropyrrolo[3,4-b]pyrrole;    -   5-((1-benzylpiperidin-4-yl)methyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole;    -   1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-phenylbutyl)octahydropyrrolo[3,4-b]pyrrole;    -   5-(adamantan-2-ylmethyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole;    -   1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-(2-phenylpropypoctahydropyrrolo[3,4-b]pyrrole;    -   (Z)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-(hept-4-en-1-yl)octahydropyrrolo[3,4-b]pyrrole;    -   1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-hexyloctahydropyrrolo[3,4-b]pyrrole;    -   1-(6-(1,4-dimethyl-        1H-pyrazol-5-yl)pyridazin-3-yl)-5-(2,2-diphenylethyl)octahydropyrrolo[3,4-b]pyrrole;    -   5-(adamantan-1-ylmethyl)-1-(6-(4-ethylpyridin-3-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole;        and    -   5-(adamantan-1-ylmethyl)-1-(6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole,    -   5-(adamantan-1-ylmethyl)-1-(6-(2-chloro-5-fluorophenyl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole;    -   5-(adamantan-1-ylmethyl)-1-(6-(2-chloro-4-fluorophenyl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole;    -   5-(adamantan-1-ylmethyl)-1-(6-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole;    -   1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-(3,3-dimethylbutyl)octahydropyrrolo[3,4-b]pyrrole;    -   (3aR,6aR)-5-(adamantan-1-ylmethyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole;    -   1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-((tetrahydro-2H-pyran-4-yl)methyl)octahydropyrrolo[3,4-b]pyrrole;        and    -   (3aS,6aS)-5-(adamantan-1-ylmethyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole,    -   or a pharmaceutically acceptable salt thereof.

Compound names are assigned by using the Struct=Name naming algorithm aspart of CHEMDRAW® ULTRA v. 12.0.

The compound may exist as a stereoisomer wherein asymmetric or chiralcenters are present. The stereoisomer is “R” or “S” depending on theconfiguration of substituents around the chiral carbon atom. The terms“R” and “S” used herein are configurations as defined in IUPAC 1974Recommendations for Section E, Fundamental Stereochemistry, in PureAppl. Chem., 1976, 45: 13-30. The disclosure contemplates variousstereoisomers and mixtures thereof and these are specifically includedwithin the scope of this invention. Stereoisomers include enantiomersand diastereomers, and mixtures of enantiomers or diastereomers.Individual stereoisomers of the compounds may be prepared syntheticallyfrom commercially available starting materials, which contain asymmetricor chiral centers or by preparation of racemic mixtures followed bymethods of resolution well-known to those of ordinary skill in the art.These methods of resolution are exemplified by (1) attachment of amixture of enantiomers to a chiral auxiliary, separation of theresulting mixture of diastereomers by recrystallization orchromatography and optional liberation of the optically pure productfrom the auxiliary as described in Furniss, Hannaford, Smith, andTatchell, “Vogel's Textbook of Practical Organic Chemistry,” 5th edition(1989), Longman Scientific & Technical, Essex CM20 2JE, England, or (2)direct separation of the mixture of optical enantiomers on chiralchromatographic columns, or (3) fractional recrystallization methods.

It should be understood that the compound may possess tautomeric forms,as well as geometric isomers, and that these also constitute embodimentsof the disclosure.

The present disclosure also includes an isotopically-labeled compound,which is identical to those recited in formula (I), but for the factthat one or more atoms are replaced by an atom having an atomic mass ormass number different from the atomic mass or mass number usually foundin nature. Examples of isotopes suitable for inclusion in the compoundsof the invention are hydrogen, carbon, nitrogen, oxygen, phosphorus,sulfur, fluorine, and chlorine, such as, but not limited to ²H, ³H, ¹³C,¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³² P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.Substitution with heavier isotopes such as deuterium, i.e. ²H, canafford certain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements and, hence, may be preferred in some circumstances. Thecompound may incorporate positron-emitting isotopes for medical imagingand positron-emitting tomography (PET) studies for determining thedistribution of receptors. Suitable positron-emitting isotopes that canbe incorporated in compounds of formula (I) are ¹¹C, ¹³N, ¹⁵O, and ¹⁸F.Isotopically-labeled compounds of formula (I) can generally be preparedby conventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying Examplesusing appropriate isotopically-labeled reagent in place ofnon-isotopically-labeled reagent.

-   -   a. Pharmaceutically Acceptable Salts

The disclosed compounds may exist as pharmaceutically acceptable salts.The term “pharmaceutically acceptable salt” refers to salts orzwitterions of the compounds which are water or oil-soluble ordispersible, suitable for treatment of disorders without undue toxicity,irritation, and allergic response, commensurate with a reasonablebenefit/risk ratio and effective for their intended use. The salts maybe prepared during the final isolation and purification of the compoundsor separately by reacting an amino group of the compounds with asuitable acid. For example, a compound may be dissolved in a suitablesolvent, such as but not limited to methanol and water and treated withat least one equivalent of an acid, like hydrochloric acid. Theresulting salt may precipitate out and be isolated by filtration anddried under reduced pressure. Alternatively, the solvent and excess acidmay be removed under reduced pressure to provide a salt. Representativesalts include acetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,formate, isethionate, fumarate, lactate, maleate, methanesulfonate,naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate,persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivalate,propionate, succinate, tartrate, trichloroacetate, trifluoroacetate,glutamate, para-toluenesulfonate, undecanoate, hydrochloric,hydrobromic, sulfuric, phosphoric and the like. The amino groups of thecompounds may also be quaternized with alkyl chlorides, bromides andiodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl,myristyl, stearyl and the like.

Basic addition salts may be prepared during the final isolation andpurification of the disclosed compounds by reaction of a carboxyl groupwith a suitable base such as the hydroxide, carbonate, or bicarbonate ofa metal cation such as lithium, sodium, potassium, calcium, magnesium,or aluminum, or an organic primary, secondary, or tertiary amine.Quaternary amine salts can be prepared, such as those derived frommethylamine, dimethylamine, trimethylamine, triethylamine, diethylamine,ethylamine, tributylamine, pyridine, N,N-dimethylaniline,N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine,dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine andN,N′-dibenzylethylenediamine, ethylenediamine, ethanolamine,diethanolamine, piperidine, piperazine, and the like.

-   -   b. General Synthesis

Compounds of formula (I) may be prepared by synthetic processes or bymetabolic processes. Preparation of the compounds by metabolic processesincludes those occurring in the human or animal body (in vivo) orprocesses occurring in vitro.

Compounds of formula (I) can be synthesized as shown in Scheme 1.

As shown in Scheme 1, tert-butylhexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (oroctahydropyrrolo[3A-b]pyrrole with another suitable protecting group atthe 5-position) can be reacted with 3,6-dichloropyridazine to generatecompound A. A Suzuki coupling with an appropriate boronic acid or esterin the presence of a palladium catalyst can provide compound B.Deprotection of compound B, followed by reaction with a suitablealdehyde in the presence of a. reducing agent, provides a compound offormula (Ia) (wherein R² and R³ are hydrogen).

The compounds and intermediates may be isolated and purified by methodswell-known to those skilled in the art of organic synthesis. Examples ofconventional methods for isolating and purifying compounds can include,but are not limited to, chromatography on solid supports such as silicagel, alumina, or silica derivatized with alkylsilane groups, byrecrystallization at high or low temperature with an optionalpretreatment with activated carbon, thin-layer chromatography,distillation at various pressures, sublimation under vacuum, andtrituration, as described for instance in “Vogel's Textbook of PracticalOrganic Chemistry,” 5th edition (1989), by Furniss, Hannaford, Smith,and Tatchell, pub. Longman Scientific & Technical, Essex CM202JE,England.

A disclosed compound may have at least one basic nitrogen whereby thecompound can be treated with an acid to form a desired salt. Forexample, a compound may be reacted with an acid at or above roomtemperature to provide the desired salt, which is deposited, andcollected by filtration after cooling. Examples of acids suitable forthe reaction include, but are not limited to tartaric acid, lactic acid,succinic acid, as well as mandelic, atrolactic, methanesulfonic,ethanesulfonic, toluenesulfonic, naphthalenesulfonic, benzenesulfonic,carbonic, fumaric, maleic, gluconic, acetic, propionic, salicylic,hydrochloric, hydrobromic, phosphoric, sulfuric, citric, hydroxybutyric,camphorsulfonic, malic, phenylacetic, aspartic, or glutamic acid, andthe like.

Reaction conditions and reaction times for each individual step can varydepending on the particular reactants employed and substituents presentin the reactants used. Specific procedures are provided in the Examplessection. Reactions can be worked up in the conventional manner, e.g. byeliminating the solvent from the residue and further purified accordingto methodologies generally known in the art such as, but not limited to,crystallization, distillation, extraction, trituration andchromatography. Unless otherwise described, the starting materials andreagents are either commercially available or can be prepared by oneskilled in the art from commercially available materials using methodsdescribed in the chemical literature. Starting materials, if notcommercially available, can be prepared by procedures selected fromstandard organic chemical techniques, techniques that are analogous tothe synthesis of known, structurally similar compounds, or techniquesthat are analogous to the above described schemes or the proceduresdescribed in the synthetic examples section.

Routine experimentations, including appropriate manipulation of thereaction conditions, reagents and sequence of the synthetic route,protection of any chemical functionality that cannot be compatible withthe reaction conditions, and deprotection at a suitable point in thereaction sequence of the method are included in the scope of theinvention. Suitable protecting groups and the methods for protecting anddeprotecting different substituents using such suitable protectinggroups are well known to those skilled in the art; examples of which canbe found in P G M Wuts and T W Greene, in Greene's book titledProtective Groups in Organic Synthesis (4^(th) ed.), John Wiley & Sons,NY (2006), which is incorporated herein by reference in its entirety.Synthesis of the compounds of the invention can be accomplished bymethods analogous to those described in the synthetic schemes describedhereinabove and in specific examples.

When an optically active form of a disclosed compound is required, itcan be obtained by carrying out one of the procedures described hereinusing an optically active starting material (prepared, for example, byasymmetric induction of a suitable reaction step), or by resolution of amixture of the stereoisomers of the compound or intermediates using astandard procedure (such as chromatographic separation,recrystallization or enzymatic resolution).

Similarly, when a pure geometric isomer of a compound is required, itcan be obtained by carrying out one of the above procedures using a puregeometric isomer as a starting material, or by resolution of a mixtureof the geometric isomers of the compound or intermediates using astandard procedure such as chromatographic separation.

It can be appreciated that the synthetic schemes and specific examplesas described are illustrative and are not to be read as limiting thescope of the invention as it is defined in the appended claims. Allalternatives, modifications, and equivalents of the synthetic methodsand specific examples are included within the scope of the claims.

-   -   c. Muscarinic Acetylcholine Receptor M₄ Activity

M₄ is the most highly expressed mAChR subtype in the striatum and itsexpression is similar in rodents and primates. Due to a lack ofselective M₄ antagonists, mechanistic understanding of the role of M₄has been guided by biochemical and genetic studies, as well as the useof highly selective M₄ positive allosteric modulators (PAMs). Highlyselective M₄ PAMs induce robust decreases in behavioral responses topsychomotor stimulants that act by increasing striatal DA levels.Furthermore, genetic deletion of M₄ increases exploratory locomotoractivity, potentiates locomotor responses to amphetamine and otherstimulants, and eliminates effects of M₄ PAMs on locomotor activity andthese effects are also observed with selective deletion of M₄ fromstriatal spiny projection neurons that express the D1 subtype of DAreceptor (D1-SPNs). In vivo microdialysis studies reveal thatadministration of M₄ PAMs reduces amphetamine-induced DA release in thedorsal and ventral striatum and fMRI studies show that M₄ PAMs reverseamphetamine-induced increases in cerebral blood flow (CBV) in striatumand other basal ganglia nuclei. More recently, fast-scanning cyclicvoltammetry (FSCV) and genetic studies, demonstrated that M₄ PAMs act,at least in part, by inhibition of DA release from presynaptic DAterminals in the striatum through release of an endocannabinoid fromstriatal spiny projection neurons (SPNs) and activation of CB2cannabinoid receptors on DA terminals.

M₄ is heavily expressed in a subset of SPNs that also express the D₁subtype of DA receptor (D₁DR), which form the direct pathway (D1-SPNs)sending inhibitory projections to the substantia nigra pars reticulata(SNr). Interestingly, D₁DRs activate a unique GTP-binding protein inD1-SPNs, termed G_(αolf) that couples D₁Rs to activation of adenylylcyclase, formation of cAMP, and activation of protein kinase A (PKA).This signaling pathway is critical for many of the behavioral actions ofDA-mediated activation of motor activity Interestingly, M₄ couples toGα_(i/o) G proteins, which inhibit adenylyl cyclase and have thepotential to directly counteract inhibit D₁ receptor signaling andeffects on motor function. These studies raise the possibility that, inaddition to inhibition of DA release, M₄ PAMs may directly inhibitDlR-mediated signaling in D₁-SPNs by direct inhibition of cAMP formationand this could also contribute to the powerful inhibitory effect ofselective M₄ activation of DA signaling in the basal ganglia. Consistentwith this, M₄ PAMs inhibit locomotor-stimulating effects of a directacting D₁ agonist. Furthermore, a series of pharmacological, genetic,and molecular/cellular studies reveal that this response is mediated byinhibition of D₁DR signaling in D1-SPNs. Thus, the primary action of M₄PAMs on D₁DR signaling is not in the striatum, but on GABAergicterminals of D₁-SPNs in the SNr, where activation of D₁DRs induces arobust increase in GABA release. This challenges the widespread viewthat cholinergic regulation of striatal function is almost exclusivelymediated through ACh released from tonically active, striatalcholinergic interneurons (ChIs) and raises the possibility thatcholinergic innervation of the SNr from cholinergic projections from thepedunculopontine nucleus may also play a critical role in regulatingmotor activity and other functions of the basal ganglia direct pathway.Together, these data suggest that in addition to inhibiting DA release,M₄ activation also acts postsynaptically in D₁-expressing SPNs toinhibit motor function.

Consistent with a prominent role of M₄ as the primary mAChR subtypeinvolved in regulating motor function, multiple reports indicate thatthe locomotor-activating effects of the mAChR antagonist scopolamine aredramatically reduced in M₄ knockout mice, but not the other four mAChRsubtypes (M_(1-3,5)). Furthermore, haloperidol-induced catalepsy, amodel of parkinsonian motor disability, is reduced in M₄ knockout miceas compared to wild-type controls. Evaluation of the anti-parkinsonianeffects of scopolamine, by assessing effects of this compound oncatalepsy induced by the DA receptor antagonist haloperidol, displayrobust catalepsy that was completely reversed by scopolamine in WT mice.The reversal by scopolamine was uncommonly robust and more pronouncedthan we observe with agents targeting a number of other targets beingevaluated for potential antiparkinsonian effects, including metabotropicglutamate (mGlu) receptors mGlu₄ or mGlu₅, A₂A adenosine receptors, andNMDA receptors. Importantly, scopolamine was ineffective in reducingcatalepsy in M₄ KO mice, suggesting that the anti-cataleptic effect ofscopolamine requires actions on mAChR M₄. Taken together with theextensive studies of M₄ modulation of basal ganglia and motor function,these studies provide compelling evidence that M₄ is the dominant mAChRsubtype involved in the antiparkinsonian effects of non-selective mAChRantagonists and provide support for discovery and development ofselective M₄ antagonists for treatment of neurodegenerative disease suchas PD, dystonia, tardive dyskinesia and other movement disorders.

Despite advances in mAChR research, there is still a scarcity ofcompounds that are potent, efficacious and selective antagonists of theM₄ mAChR. Highly selective M₄ antagonists represent a new therapeuticapproach for the treatment of neurodegenerative diseases including PD,dystonia, tardive dyskinesia and other movement disorders and may offerthe clinical benefit of scopolamine, without the adverse effectsmediated by pan-mAChR. inhibition.

In some embodiments, the disclosed compounds are antagonists of mAChRM₄. Such activity can be demonstrated by methodology known in the art.For example, antagonism of mAChR M₄ activity can be determined bymeasurement of calcium flux in response to agonist, e.g. acetylcholine,in cells loaded with a Ca²⁺-sensitive fluorescent dye (e.g., Fluo-4) andco-expression of a chimeric or promiscuous G protein. In someembodiments, the calcium flux can be measured as an increase influorescent static ratio. In some embodiments, antagonist activity canbe analyzed as a concentration-dependent increase in the EC₈₀acetylcholine response (i.e. the response of mAChR M₄ at a concentrationof acetylcholine that yields 80% of the maximal response).

In some embodiments, the disclosed compounds antagonize mAChR M₄ as adecrease in calcium fluorescence in mAChR M₄-transfected CHO-Kl cells inthe presence of the compound, compared to the response of equivalentCHO-Kl cells in the absence of the compound. In some embodiments, adisclosed compound antagonizes the mAChR M₄ response with an IC₅₀ ofless than about 100 μM, less than about 5 μM, less than about 1 μM, lessthan about 500 nM, of less than about 100 nM, or less than about 50 nM.In some embodiments, the mAChR M₄-transfected CHO-Kl cells aretransfected with human mAChR M₄. In some embodiments, the mAChRM₄-transfected CHO-Kl cells are transfected with rat mAChR M_(4.) Insome embodiments, the mAChR M₄-transfected CHO-Kl cells are transfectedwith mAChR M₄ from dog or cynomolgus monkey.

The disclosed compounds may antagonize mAChR. M₄ response in mAChRM₄-transfected CHO-Kl cells with an IC₅₀ less than the IC₅₀ for one ormore of mAChR M₁, M_(2,) M₃ or M₅-transfected. CHO-Kl cells. That is, adisclosed compound can have selectivity for the mAChR M₄ receptorvis-a-vis one or more of the mAChR M₁, M_(2,) M₃ or M₅ receptors. Forexample, in some embodiments, a disclosed compound can antagonize mAChRM₄ response with an IC₅₀ of about 5-fold less, about 10-fold less, about20-fold less, about 30-fold less, about 50-fold less, about 100-foldless, about 200-fold less, about 300-fold less, about 400-fold less, orgreater than about 500-fold less than that for mAChR M₁. In someembodiments, a disclosed compound can antagonize mAChR M₄ response withan IC₅₀ of about 5-fold less, about 10-fold less, about 20-fold less,about 30-fold less, about 50-fold less, about 100-fold less, about200-fold less, about 300-fold less, about 400-fold less, or greater thanabout 500-fold less than that for mAChR M_(2.) In some embodiments, adisclosed compound can antagonize mAChR M₄ response with an IC₅₀ ofabout 5-fold less, about 10-fold less, about 20-fold less, about 30-foldless, about 50-fold less, about 100-fold less, about 200-fold less,about 300-fold less, about 400-fold less, or greater than about 500-foldless than that for mAChR M_(3.) In some embodiments, a disclosedcompound can antagonize mAChR M₄ response with an IC₅₀ of about 5-foldless, about 10-fold less, about 20-fold less, about 30-fold less, about50-fold less, about 100-fold less, about 200-fold less, about 300-foldless, about 400-fold less, or greater than about 500-fold less than thatfor mAChR Ms. In some embodiments, a disclosed compound can antagonizemAChR M₄ response with an IC₅₀ of 5-fold less, about 10-fold less, about20-fold less, about 30-fold less than that for the M₂-M₅ receptors, ofabout 50-fold less, about 100-fold less, about 200-fold less, about300-fold less, about 400-fold less, or greater than about 500-fold lessthan that for the mAChR M₁, M₂, M₃, or M₅ receptors.

The disclosed compounds may antagonize mAChR M₄ response inM₄-transfected CHO-Kl cells with an IC₅₀ of less than about 10 μM andexhibit a selectivity for the M₄ receptor vis-à-vis one or more of themAChR M₁, M₂, M₃, or M₅ receptors. For example, in some embodiments, thecompound can have an IC₅₀ of less than about 10 μM, of less than about 5μM, of less than about 1 μM, of less than about 500 nM, of less thanabout 100 nM, or of less than about 50 nM; and the compound can alsoantagonize mAChR M₄ response with an IC₅₀ of about 5-fold less, 10-foldless, 20-fold less, 30-fold less, 50-fold less, 100-fold less, 200-foldless, 300-fold less, 400-fold less, or greater than about 500-fold lessthan that for mAChR M₁. In some embodiments, the compound can have anIC₅₀ of less than about 10 μM, of less than about 5 μM, of less thanabout 1 μM, of less than about 500 nM, of less than about 100 nM, or ofless than about 50 nM; and the compound can also antagonize mAChR. M₄response with an IC₅₀ of about 5-fold less, about 10-fold less, about20-fold less, about 30-fold less, about 50-fold less, about 100-foldless, about 200-fold less, about 300-fold less, about 400-fold less, orgreater than about 500-fold less than that for mAChR M₂. In someembodiments, the compound can have an IC₅₀ of less than about 10 μM, ofless than about 5 μM, of less than about 1 μM, of less than about 500nM, of less than about 100 nM, or of less than about 50 nM; and thecompound can also antagonize mAChR M₄ response with an IC₅₀ of about5-fold less, about 10-fold less, about 20-fold less, about 30-fold less,about 50-fold less, about 100-fold less, about 200-fold less, about300-fold less, about 400-fold less, or greater than about 500-fold lessthan that for mAChR M₃. In some embodiments, the compound can have anIC₅₀ of less than about 10 μM, of less than about 5 μM, of less thanabout 1 μM, of less than about 500 nM, of less than about 100 nM, or ofless than about 50 nM; and the compound can also antagonize mAChR M₄response with an IC₅₀ of about 5-fold less, about 10-fold less, about20-fold less, about 30-fold less, about 50-fold less, about 100-foldless, about 200-fold less, about 300-fold less, about 400-fold less, orgreater than about 500-fold less than that for mAChR M₅. In someembodiments, the compound can have an IC₅₀ of less than about 10 μM, ofless than about 5 μM, of less than about 1 μM, of less than about 500nM, of less than about 100 nM, or of less than about 50 nM; and thecompound can also antagonize mAChR M₄ response with IC₅₀ of 5-fold less,about 10-fold less, about 20-fold less, about 30-fold less than that forthe M₂-M₅ receptors, of about 50-fold less, about 100-fold less, about200-fold less, about 300-fold less, about 400-fold less, M₂, M₃, or M₅receptors, or greater than about 500-fold less than that for the mAChRM₁, M₂, M_(3,) or M₅ receptors.

In vivo efficacy for disclosed compounds in models that predictantiparkinsonian activity can be measured in a number of preclinical ratmodels. For example, disclosed compounds may reverse deficits in motorfunction induced by the dopamine receptor antagonist in mice or rats.Also, these compounds may reverse deficits in motor function that areobserved with other manipulations that reduce dopaminergic signaling,such as selective lesions of dopamine neurons. In addition, it ispossible that these compounds will have efficacy in animal models ofdystonia and may increase attention, cognitive function, and measures ofmotivation in animal models.

3. Pharmaceutical Compositions and Formulations

The disclosed compounds may be incorporated into pharmaceuticalcompositions suitable for administration to a subject (such as apatient, which may be a human or non-human). The disclosed compounds mayalso be provided as formulations, such as spray-dried dispersionformulations.

The pharmaceutical compositions and formulations may include a“therapeutically effective amount” or a “prophylactically effectiveamount” of the agent. A “therapeutically effective amount” refers to anamount effective, at dosages and for periods of time necessary, toachieve the desired therapeutic result. A therapeutically effectiveamount of the composition may be determined by a person skilled in theart and may vary according to factors such as the disease state, age,sex, and weight of the individual, and the ability of the composition toelicit a desired response in the individual. A therapeutically effectiveamount is also one in which any toxic or detrimental effects of acompound of the invention (e.g., a compound of formula (I)) areoutweighed by the therapeutically beneficial effects. A“prophylactically effective amount” refers to an amount effective, atdosages and for periods of time necessary, to achieve the desiredprophylactic result. Typically, since a prophylactic dose is used insubjects prior to or at an earlier stage of disease, theprophylactically effective amount will be less than the therapeuticallyeffective amount.

For example, a therapeutically effective amount of a compound of formula(I), may be about 1 mg/kg to about 1000 mg/kg, about 5 mg/kg to about950 mg/kg, about 10 mg/kg to about 900 mg/kg, about 15 mg/kg to about850 mg/kg, about 20 mg/kg to about 800 mg/kg, about 25 mg/kg to about750 mg/kg, about 30 mg/kg to about 700 mg/kg, about 35 mg/kg to about650 mg/kg, about 40 mg/kg to about 600 mg/kg, about 45 mg/kg to about550 mg/kg, about 50 mg/kg to about 500 mg/kg, about 55 mg/kg to about450 mg/kg, about 60 mg/kg to about 400 mg/kg, about 65 mg/kg to about350 mg/kg, about 70 mg/kg to about 300 mg/kg, about 75 mg/kg to about250 mg/kg, about 80 mg/kg to about 200 mg/kg, about 85 mg/kg to about150 mg/kg, and about 90 mg/kg to about 100 mg/kg.

The pharmaceutical compositions and formulations may includepharmaceutically acceptable carriers. The term “pharmaceuticallyacceptable carrier,” as used herein, means a non-toxic, inert solid,semi-solid or liquid filler, diluent, encapsulating material orformulation auxiliary of any type. Some examples of materials which canserve as pharmaceutically acceptable carriers are sugars such as, butnot limited to, lactose, glucose and sucrose; starches such as, but notlimited to, corn starch and potato starch; cellulose and its derivativessuch as, but not limited to, sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin;talc; excipients such as, but not limited to, cocoa butter andsuppository waxes; oils such as, but not limited to, peanut oil,cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; glycols; such as propylene glycol; esters such as, but notlimited to, ethyl oleate and ethyl laurate; agar; buffering agents suchas, but not limited to, magnesium hydroxide and aluminum hydroxide;alginic acid; pyrogen-free water; isotonic saline; Ringer's solution;ethyl alcohol, and phosphate buffer solutions, as well as othernon-toxic compatible lubricants such as, but not limited to, sodiumlauryl sulfate and magnesium stearate, as well as coloring agents,releasing agents, coating agents, sweetening, flavoring and perfumingagents, preservatives and antioxidants can also be present in thecomposition, according to the judgment of the formulator.

Thus, the compounds and their physiologically acceptable salts may beformulated for administration by, for example, solid dosing, eye drop,in a topical oil-based formulation, injection, inhalation (eitherthrough the mouth or the nose), implants, or oral, buccal, parenteral,or rectal administration. Techniques and formulations may generally befound in “Remington's Pharmaceutical Sciences,” (Meade Publishing Co.,Easton, Pa.). Therapeutic compositions must typically be sterile andstable under the conditions of manufacture and storage.

The route by which the disclosed compounds are administered and the formof the composition will dictate the type of carrier to be used. Thecomposition may be in a variety of forms, suitable, for example, forsystemic administration (e.g., oral, rectal, nasal, sublingual, buccal,implants, or parenteral) or topical administration (e.g., dermal,pulmonary, nasal, aural, ocular, liposome delivery systems, oriontophoresis).

Carriers for systemic administration typically include at least one ofdiluents, lubricants, binders, disintegrants, colorants, flavors,sweeteners, antioxidants, preservatives, glidants, solvents, suspendingagents, wetting agents, surfactants, combinations thereof, and others.All carriers are optional in the compositions.

Suitable diluents include sugars such as glucose, lactose, dextrose, andsucrose; diols such as propylene glycol; calcium carbonate; sodiumcarbonate; sugar alcohols, such as glycerin; mannitol; and sorbitol. Theamount of diluent(s) in a systemic or topical composition is typicallyabout 50 to about 90%.

Suitable lubricants include silica, talc, stearic acid and its magnesiumsalts and calcium salts, calcium sulfate; and liquid lubricants such aspolyethylene glycol and vegetable oils such as peanut oil, cottonseedoil, sesame oil, olive oil, corn oil and oil of theobroma. The amount oflubricant(s) in a systemic or topical composition is typically about 5to about 10%.

Suitable binders include polyvinyl pyrrolidone; magnesium aluminumsilicate; starches such as corn starch and potato starch; gelatin;tragacanth; and cellulose and its derivatives, such as sodiumcarboxymethylcellulose ethyl cellulose, methylcellulose,microcrystalline cellulose, and sodium carboxymethylcellulose. Theamount of binder(s) in a systemic composition is typically about 5 toabout 50%.

Suitable disintegrants include agar, alginic acid and the sodium saltthereof, effervescent mixtures, croscarmellose, crospovidone, sodiumcarboxymethyl starch, sodium starch glycolate, clays, and ion exchangeresins. The amount of disintegrant(s) in a systemic or topicalcomposition is typically about 0.1 to about 10%.

Suitable colorants include a colorant such as an FD&C dye. When used,the amount of colorant in a systemic or topical composition is typicallyabout 0.005 to about 0.1%.

Suitable flavors include menthol, peppermint, and fruit flavors. Theamount of flavor(s), when used, in a systemic or topical composition istypically about 0.1 to about 1.0%.

Suitable sweeteners include aspartame and saccharin. The amount ofsweetener(s) in a systemic or topical composition is typically about0.001 to about 1%.

Suitable antioxidants include butylated hydroxyanisole (“BHA”),butylated hydroxytoluene (BHT), and vitamin E. The amount ofantioxidant(s) in a systemic or topical composition is typically about0.1 to about 5%.

Suitable preservatives include benzalkonium chloride, methyl paraben andsodium benzoate. The amount of preservative(s) in a systemic or topicalcomposition is typically about 0.01 to about 5%.

Suitable glidants include silicon dioxide. The amount of glidant(s) in asystemic or topical composition is typically about 1 to about 5%.

Suitable solvents include water, isotonic saline, ethyl oleate,glycerine, hydroxylated castor oils, alcohols such as ethanol, andphosphate buffer solutions. The amount of solvent(s) in a systemic ortopical composition is typically from about 0 to about 100%.

Suitable suspending agents include AVICEL RC-591 (from FMC Corporationof Philadelphia, Pa.) and sodium alginate. The amount of suspendingagent(s) in a systemic or topical composition is typically about 1 toabout 8%.

Suitable surfactants include lecithin, Polysorbate 80, and sodium laurylsulfate, and the TWEENS from Atlas Powder Company of Wilmington, Del.Suitable surfactants include those disclosed in the C.T.F.A. CosmeticIngredient Handbook, 1992, pp.587-592; Remington's PharmaceuticalSciences, 15th Ed. 1975, pp. 335-337; and McCutcheon's Volume 1,Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. Theamount of surfactant(s) in the systemic or topical composition istypically about 0.1% to about 5%.

Although the amounts of components in the systemic compositions may varydepending on the type of systemic composition prepared, in general,systemic compositions include 0.01% to 50% of an active compound (e.g.,a compound of formula (I)) and 50% to 99.99% of one or more carriers.Compositions for parenteral administration typically include 0.1% to 10%of actives and 90% to 99,9% of a carrier including a diluent and asolvent.

Compositions for oral administration can have various dosage forms. Forexample, solid forms include tablets, capsules, granules, and bulkpowders. These oral dosage forms include a safe and effective amount,usually at least about 5%, and more particularly from about 25% to about50% of actives. The oral dosage compositions include about 50% to about95% of carriers, and more particularly, from about 50% to about 75%.

Tablets can be compressed, tablet triturates, enteric-coated,sugar-coated, film-coated, or multiple-compressed. Tablets typicallyinclude an active component, and a carrier comprising ingredientsselected from diluents, lubricants, binders, disintegrants, colorants,flavors, sweeteners, glidants, and combinations thereof. Specificdiluents include calcium carbonate, sodium carbonate, mannitol, lactoseand cellulose. Specific binders include starch, gelatin, and sucrose.Specific disintegrants include alginic acid and croscarmellose. Specificlubricants include magnesium stearate, stearic acid, and talc. Specificcolorants are the FD&C dyes, which can be added for appearance. Chewabletablets preferably contain sweeteners such as aspartame and saccharin,or flavors such as menthol, peppermint, fruit flavors, or a combinationthereof.

Capsules (including implants, time release and sustained releaseformulations) typically include an active compound (e.g., a compound offormula (I)), and a carrier including one or more diluents disclosedabove in a capsule comprising gelatin. Granules typically comprise adisclosed compound, and preferably glidants such as silicon dioxide toimprove flow characteristics. Implants can be of the biodegradable orthe non-biodegradable type.

The selection of ingredients in the carrier for oral compositionsdepends on secondary considerations like taste, cost, and shelfstability, which are not critical for the purposes of this invention.

Solid compositions may be coated by conventional methods, typically withpH or time-dependent coatings, such that a disclosed compound isreleased in the gastrointestinal tract in the vicinity of the desiredapplication, or at various points and times to extend the desiredaction. The coatings typically include one or more components selectedfrom the group consisting of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethylcellulose, EUDRAGIT® coatings (available from Evonik Industries ofEssen, Germany), waxes and shellac.

Compositions for oral administration can have liquid forms. For example,suitable liquid forms include aqueous solutions, emulsions, suspensions,solutions reconstituted from non-effervescent granules, suspensionsreconstituted from non-effervescent granules, effervescent preparationsreconstituted from effervescent granules, elixirs, tinctures, syrups,and the like. Liquid orally administered compositions typically includea disclosed compound and a carrier, namely, a carrier selected fromdiluents, colorants, flavors, sweeteners, preservatives, solvents,suspending agents, and surfactants. Peroral liquid compositionspreferably include one or more ingredients selected from colorants,flavors, and sweeteners.

Other compositions useful for attaining systemic delivery of the subjectcompounds include sublingual, buccal and nasal dosage forms. Suchcompositions typically include one or more of soluble filler substancessuch as diluents including sucrose, sorbitol and mannitol; and binderssuch as acacia, microcrystalline cellulose, carboxymethyl cellulose, andhydroxypropyl methylcellulose. Such compositions may further includelubricants, colorants, flavors, sweeteners, antioxidants, and glidants.

The disclosed compounds can be topically administered. Topicalcompositions that can be applied locally to the skin may be in any formincluding solids, solutions, oils, creams, ointments, gels, lotions,shampoos, leave-on and rinse-out hair conditioners, milks, cleansers,moisturizers, sprays, skin patches, and the like. Topical compositionsinclude: a disclosed compound (e.g., a compound of formula (I)), and acarrier. The carrier of the topical composition preferably aidspenetration of the compounds into the skin. The carrier may furtherinclude one or more optional components.

The amount of the carrier employed in conjunction with a disclosedcompound is sufficient to provide a practical quantity of compositionfor administration per unit dose of the compound. Techniques andcompositions for making dosage forms useful in the methods of thisinvention are described in the following references: ModernPharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979);Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); andAnsel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).

A carrier may include a single ingredient or a combination of two ormore ingredients. In the topical compositions, the carrier includes atopical carrier. Suitable topical carriers include one or moreingredients selected from phosphate buffered saline, isotonic water,deionized water, monofunctional alcohols, symmetrical alcohols, aloevera gel, allantoin, glycerin, vitamin A and E oils, mineral oil,propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castoroil, combinations thereof, and the like. More particularly, carriers forskin applications include propylene glycol, dimethyl isosorbide, andwater, and even more particularly, phosphate buffered saline, isotonicwater, deionized water, monofunctional alcohols, and symmetricalalcohols.

The carrier of a topical composition may further include one or moreingredients selected from emollients, propellants, solvents, humectants,thickeners, powders, fragrances, pigments, and preservatives, all ofwhich are optional.

Suitable emollients include stearyl alcohol, glyceryl monoricinoleate,glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil,cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate,isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate,decyl oleate, octadecan-2-ol, isocetyl alcohol, cetyl palmitate,di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropylstearate, butyl stearate, polyethylene glycol, triethylene glycol,lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylatedlanolin alcohols, petroleum, mineral oil, butyl myristate, isostearicacid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyllactate, decyl oleate, myristyl myristate, and combinations thereof.Specific emollients for skin include stearyl alcohol andpolydimethylsiloxane. The amount of emollient(s) in a skin-based topicalcomposition is typically about 5% to about 95%.

Suitable propellants include propane, butane, isobutane, dimethyl ether,carbon dioxide, nitrous oxide, and combinations thereof. The amount ofpropellant(s) in a topical composition is typically about 0% to about95%.

Suitable solvents include water, ethyl alcohol, methylene chloride,isopropanol, castor oil, ethylene glycol monoethyl ether, diethyleneglycol monobutyl ether, diethylene glycol monoethyl ether,dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, and combinationsthereof. Specific solvents include ethyl alcohol and homotopic alcohols.The amount of solvent(s) in a topical composition is typically about 0%to about 95%.

Suitable humectants include glycerin, sorbitol, sodium2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate,gelatin, and combinations thereof. Specific humectants include glycerin.The amount of humectant(s) in a topical composition is typically 0% to95%.

The amount of thickener(s) in a topical composition is typically about0% to about 95%.

Suitable powders include beta-cyclodextrins, hydroxypropylcyclodextrins, chalk, talc, fullers earth, kaolin, starch, gums,colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammoniumsmectites, trialkyl aryl ammonium smectites, chemically-modifiedmagnesium aluminum silicate, organically-modified montmorillonite clay,hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodiumcarboxymethyl cellulose, ethylene glycol monostearate, and combinationsthereof. The amount of powder(s) in a topical composition is typically0% to 95%.

The amount of fragrance in a topical composition is typically about 0%to about 0.5%, particularly, about 0.001% to about 0.1%.

Suitable pH adjusting additives include HO or NaOH in amounts sufficientto adjust the pH of a topical pharmaceutical composition.

The pharmaceutical composition or formulation may antagonize mAChR M₄with an IC₅₀ of less than about 10 μM, less than about 5 μM, less thanabout 1 μM, less than about 500 nM, or less than about 100 nM. Thepharmaceutical composition or formulation may antagonize mAChR M₄ withan IC₅₀ of between about 10 μM and about 1 nM, about 1 μM and about 1nM, about 100 nM and about 1 nM, or between about 10 nM and about 1 nM.

-   -   a. Spray-Dried Dispersion Formulations

The disclosed compounds may be formulated as a spray-dried dispersion(SDD). An SDD is a single-phase, amorphous molecular dispersion of adrug in a polymer matrix. It is a solid solution with the compoundmolecularly “dissolved” in a solid matrix. SDDs are obtained bydissolving drug and a polymer in an organic solvent and thenspray-drying the solution. The use of spray drying for pharmaceuticalapplications can result in amorphous dispersions with increasedsolubility of Biopharmaceutics Classification System (BCS) class II,(high permeability, low solubility) and class IV (low permeability, lowsolubility) drugs. Formulation and process conditions are selected sothat the solvent quickly evaporates from the droplets, thus allowinginsufficient time for phase separation or crystallization, SDDs havedemonstrated long-term stability and manufacturability. For example,shelf lives of more than 2 years have been demonstrated with SDDs.Advantages of SDDs include, but are not limited to, enhanced oralbioavailability of poorly water-soluble compounds, delivery usingtraditional solid dosage forms (e.g., tablets and capsules), areproducible, controllable and scalable manufacturing process and broadapplicability to structurally diverse insoluble compounds with a widerange of physical properties.

Thus, in one embodiment, the disclosure may provide a spray-drieddispersion formulation comprising a compound of formula (1).

4. Methods of Use

The disclosed compounds, pharmaceutical compositions and formulationsmay be used in methods for treatment of disorders, such as neurologicaland/or psychiatric disorders, associated with muscarinic acetylcholinereceptor dysfunction. The disclosed compounds and pharmaceuticalcompositions may also be used in methods for decreasing muscarinicacetylcholine receptor activity in a mammal. The methods further includecotherapeutic methods for improving treatment outcomes. In the methodsof use described herein, additional therapeutic agent(s) may beadministered simultaneously or sequentially with the disclosed compoundsand compositions.

-   -   a. Treating Disorders

The disclosed compounds, pharmaceutical compositions and formulationsmay be used in methods for treating, preventing, ameliorating,controlling, reducing, or reducing the risk of a variety of disorders,or symptoms of the disorders, in which a patient would benefit fromantagonism of mAChR M_(4.) In some embodiments, the disorder may be aneurodegenerative disorder, a movement disorder, or a brain disorder.The methods may comprise administering to a subject in need of suchtreatment a therapeutically effective amount of the compound of formula(I) or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt thereof.

Disorders in which a patient would benefit from antagonism of mAChR M₄may include neurodegenerative disorders and movement disorders. Forexample, exemplary disorders may include Parkinson's disease,drug-induced Parkinsonism, dystonia, Tourette's syndrome, dyskinesias(e.g., tardive dyskinesia or levodopa-induced dyskinesia),schizophrenia, cognitive deficits associated with schizophrenia,excessive daytime sleepiness (e.g., narcolepsy), attention deficithyperactivity disorder (ADHD), Huntington's disease, chorea (e.g.,chorea associated with Huntington's disease), cerebral palsy, andprogressive supranuclear palsy.

In some embodiments, the disclosure provides a method for treating motorsymptoms in a subject having Parkinson's disease, comprisingadministering to a subject in need thereof a therapeutically effectiveamount of the compound of formula. (I) or a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition comprising atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof. In some embodiments, the motorsymptoms are selected from bradykinesia, tremor, rigidity, gaitdysfunction, and postural instability. The method may treat the motorsymptoms, control the motor symptoms, and/or reduce the motor symptomsin the subject.

In some embodiments, the disclosure provides a method for treating motorsymptoms in a subject having dystonia, comprising administering to thesubject a therapeutically effective amount of the compound of formula(1) or a pharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof formula (1) or a pharmaceutically acceptable salt thereof. The methodmay treat the motor symptoms, control the motor symptoms, and/or reducethe motor symptoms in the subject. For example, treatment may reducemuscle contractions or spasms in a subject having dystonia.

In some embodiments, the disclosure provides a method for treating motorsymptoms in a subject having tardive dyskinesia, comprisingadministering to the subject a therapeutically effective amount of thecompound of formula (I) or a pharmaceutically acceptable salt thereof,or a pharmaceutical composition comprising a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof. The method may treat the motor symptoms, control the motorsymptoms, and/or reduce the motor symptoms in the subject. For example,treatment may reduce involuntary movements in a subject having tardivedyskinesia.

In some embodiments, the disclosure provides a method of preventing ordelaying tardive dyskinesia in a subject at risk of developing tardivedyskinesia, comprising administering to the subject a therapeuticallyeffective amount of the compound of formula (I) or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition comprising atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof. For example, the subject maybe a subject being treated with a neuroleptic medication (e.g., atypical antipsychotic or an atypical antipsychotic), a dopamineantagonist, or an antiemetic.

In some embodiments, the disclosure provides a method of treatingcatalepsy in a subject suffering from schizophrenia, comprisingadministering to the subject a therapeutically effective amount of thecompound of formula (I) or a pharmaceutically acceptable salt thereof,or a pharmaceutical composition comprising a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof. For example, the subject suffering from schizophrenia mayhave catalepsy induced by a neuroleptic agent (e.g., a typicalantipsychotic or an atypical antipsychotic).

In some embodiments, the disclosure provides a method of treating abrain disorder characterized by altered dopamine and cholinergicsignaling that could benefit from antagonism of mAChR M_(4,) comprisingadministering to the subject a therapeutically effective amount of thecompound of formula (I) or a pharmaceutically acceptable salt thereof,or a pharmaceutical composition comprising a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof For example, the treatment may increase motivation orgoal-directed behavior in patients suffering from disorderscharacterized by reduced motivation for goal-directed behavior, such asschizophrenia and other brain disorders.

In some embodiments, the disclosure provides a method for increasingwakefulness and/or reducing excessive daytime sleepiness in a subject inneed thereof, comprising administering to the subject a therapeuticallyeffective amount of the compound of formula (I) or a pharmaceuticallyacceptable salt thereof, or a pharmaceutical composition comprising atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof. In some embodiments, thesubject is a subject suffering from narcolepsy.

In some embodiments, the disclosure provides a method of increasingattention in a subject (e.g., a subject suffering from an attentiondeficit disorder such as ADHD) in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of thecompound of formula (I) or a pharmaceutically acceptable salt thereof,or a pharmaceutical composition comprising a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof

In some embodiments, the disclosure provides a method for treating motorsymptoms in a subject having a drug-induced movement disorder,comprising administering the subject a. therapeutically effective amountof the compound of formula (I) or a pharmaceutically acceptable saltthereof, or a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof. In sonic embodiments, the drug-induced movementdisorder is selected from drug-induced parkinsonism, tardive dyskinesia,tardive dystonia, akathisia, myoclonus, and tremor. The method may treatthe motor symptoms, control the motor symptoms, and/or reduce the motorsymptoms in the subject.

The compounds and compositions may be further useful in a method for theprevention, treatment, control, amelioration, or reduction of risk ofthe diseases, disorders and conditions noted herein. The compounds andcompositions may be further useful in a method for the prevention,treatment, control, amelioration, or reduction of risk of theaforementioned diseases, disorders and conditions, in combination withother agents.

In the treatment of conditions such as those that would benefit fromantagonism of mAChR M_(4,) an appropriate dosage level may be about 0.01to 500 mg per kg patient body weight per day, which can be administeredin single or multiple doses. The dosage level may be about 0.1 to about250 mg/kg per day, or about 0.5 to about 100 mg/kg per day. A suitabledosage level can be about 0.01 to 250 mg/kg per day, about 0.05 to 100mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range thedosage can be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oraladministration, the compositions may be provided in the form of tabletscontaining 1.0 to 1000 milligrams of the active ingredient, particularly1.0, 5.0, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500,600, 750, 800, 900, or 1000 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Thecompounds can be administered on a regimen of 1 to 4 times per day,preferably once or twice per day. This dosage regimen can be adjusted toprovide the optimal therapeutic response. It will be understood,however, that the specific dose level and frequency of dosage for anyparticular patient can be varied and will depend upon a variety offactors including the activity of the specific compound employed, themetabolic stability and length of action of that compound, the age, bodyweight, general health, sex, diet, mode and time of administration, rateof excretion, drug combination, the severity of the particularcondition, and the host undergoing therapy.

Thus, in some embodiments, the disclosure relates to a method forantagonizing the mAChR M₄ receptor in at least one cell, comprising thestep of contacting the at least one cell with at least one disclosedcompound or at least one product of a disclosed method in an amounteffective to antagonize mAChR M₄ in the at least one cell. In someembodiments, the cell is mammalian, for example, human. In someembodiments, the cell has been isolated from a subject prior to thecontacting step. In some embodiments, contacting is via administrationto a subject.

In some embodiments, the invention relates to a method for antagonizingthe mAChR M₄ receptor in a subject, comprising the step of administeringto the subject at least one disclosed compound or at least one productof a disclosed method in a dosage and amount effective to antagonize themAChR M₄ receptor in the subject. In some embodiments, the subject ismammalian, for example, human. In some embodiments, the mammal has beendiagnosed with a need for mAChR M₄ antagonism prior to the administeringstep. In some embodiments, the mammal has been diagnosed with a need formAChR M₄ antagonism prior to the administering step. In someembodiments, the method further comprises the step of identifying asubject in need of mAChR M₄ antagonism.

-   -   b. Antagonism of the Muscarinic Acetylcholine Receptor

In some embodiments, the disclosure relates to a method for antagonizingmAChR M₄ in a mammal, comprising the step of administering to the mammalan effective amount of at least one disclosed compound or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition comprising at least one disclosed compound orpharmaceutically acceptable salt thereof.

In some embodiments, antagonism of the muscarinic acetylcholine receptordecreases muscarinic acetylcholine receptor activity.

In some embodiments, the compound administered antagonizes mAChR M₄ withan IC₅₀ of less than about 10 μM, less than about 5 less than about 1less than about 500 nM, or less than about 100 nM. In some embodiments,the compound administered antagonizes mAChR M₄ with an IC₅₀ of betweenabout 10 μM and about 1 nM, about 1 μM and about 1 nM, about 100 nM andabout 1 nM, or about 10 nM and about 1 nM.

In some embodiments, the mammal is a human. In some embodiments, themammal has been diagnosed with a need for reduction of muscarinicacetylcholine receptor activity prior to the administering step. In someembodiments, the method further comprises the step of identifying amammal in need of reducing muscarinic acetylcholine receptor activity.In some embodiments, the antagonism of the muscarinic acetylcholinereceptor treats a disorder associated with muscarinic acetylcholinereceptor activity in the mammal. In some embodiments, the muscarinicacetylcholine receptor is mAChR M₄.

In some embodiments, antagonism of the muscarinic acetylcholine receptorin a mammal is associated with the treatment of a disorder associatedwith a muscarinic receptor dysfunction, such as a disorder disclosedherein. In sonic embodiments, the muscarinic receptor is mAChR M₄.

In some embodiments, the disclosure provides a method for antagonizingthe muscarinic acetylcholine receptor in a cell, comprising the step ofcontacting the cell with an effective amount of at least one disclosedcompound or a pharmaceutically acceptable salt thereof. In someembodiments, the cell is mammalian (e.g., human). In some embodiments,the cell has been isolated from a mammal prior to the contacting step.In some embodiments, contacting is via administration to a mammal.

-   -   c. Cotherapeutic Methods

The present disclosure is further directed to administration of a mAChRM₄ antagonist, such as a selective mAChR M₄ antagonist, for improvingtreatment outcomes. That is, in some embodiments, the disclosure relatesto a cotherapeutic method comprising a step of administering to a mammalan effective amount and dosage of at least one disclosed compound, or apharmaceutically acceptable salt thereof.

In some embodiments, administration improves treatment outcomes in thecontext of cognitive or behavioral therapy. Administration in connectionwith cognitive or behavioral therapy can be continuous or intermittent.Administration need not be simultaneous with therapy and can be before,during, and/or after therapy. For example, cognitive or behavioraltherapy can be provided within 1, 2, 3, 4, 5, 6, 7 days before or afteradministration of the compound. As a further example, cognitive orbehavioral therapy can be provided within 1, 2, 3, or 4 weeks before orafter administration of the compound. As a still further example,cognitive or behavioral therapy can be provided before or afteradministration within a period of time of 1, 2, 3, 4, 5, 6, 7, 8, 9, or10 half-lives of the administered compound,

In some embodiments, administration may improve treatment outcomes inthe context of physical or occupational therapy. Administration inconnection with physical or occupational therapy can be continuous orintermittent. Administration need not be simultaneous with therapy andcan he before, during, and/or after therapy. For example, physical oroccupational therapy can be provided within 1, 2, 3, 4, 5, 6, 7 daysbefore or after administration of the compound. As a further example,physical or occupational therapy can be provided within 1, 2, 3, or 4weeks before or after administration of the compound. As a still furtherexample, physical or occupational therapy can he provided before orafter administration within a period of time of 1, 2, 3, 4, 5, 6, 7, 8,9, or 10 half-lives of the administered compound.

It is understood that the disclosed cotherapeutic methods can be used inconnection with the disclosed compounds, compositions, kits, and uses.

-   -   d. Combination Therapies

In the methods of use described herein, additional therapeutic agent(s)may be administered simultaneously or sequentially with the disclosedcompounds and compositions. Sequential administration includesadministration before or after the disclosed compounds and compositions.In some embodiments, the additional therapeutic agent or agents may beadministered in the same composition as the disclosed compounds. Inother embodiments, there may be an interval of time betweenadministration of the additional therapeutic agent and the disclosedcompounds. In some embodiments, administration of an additionaltherapeutic agent with a disclosed compound may allow lower doses of theother therapeutic agents and/or administration at less frequentintervals. When used in combination with one or more other activeingredients, the compounds of the present invention and the other activeingredients may be used in lower doses than when each is used singly.Accordingly, the pharmaceutical compositions of the present inventioninclude those that contain one or more other active ingredients, inaddition to a compound of Formula (I). The above combinations includecombinations of a compound of the present invention not only with oneother active compound, but also with two or more other active compounds.

The disclosed compounds can be used as single agents or in combinationwith one or more other drugs in the treatment, prevention, control,amelioration or reduction of risk of the aforementioned diseases,disorders and conditions for which the compound or the other drugs haveutility, where the combination of drugs together are safer or moreeffective than either drug alone. The other drug(s) can be administeredby a route and in an amount commonly used therefor, contemporaneously orsequentially with a disclosed compound. When a disclosed compound isused contemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such drugs and the disclosedcompound may be used. However, the combination therapy can also beadministered on overlapping schedules. It is also envisioned that thecombination of one or more active ingredients and a disclosed compoundcan be more efficacious than either as a single agent. Thus, when usedin combination with one or more other active ingredients, the disclosedcompounds and the other active ingredients can be used in lower dosesthan when each is used singly.

The pharmaceutical compositions and methods of the present invention canfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of the above mentionedpathological conditions.

The above combinations include combinations of a disclosed compound notonly with one other active compound, but also with two or more otheractive compounds. Likewise, disclosed compounds can be used incombination with other drugs that are used in the prevention, treatment,control, amelioration, or reduction of risk of the diseases orconditions for which disclosed compounds are useful. Such other drugscan be administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound of the presentinvention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to a disclosedcompound is preferred. Accordingly, the pharmaceutical compositionsinclude those that also contain one or more other active ingredients, inaddition to a compound of the present invention.

The weight ratio of a disclosed compound to the second active ingredientcan be varied and will depend upon the effective dose of eachingredient. Generally, an effective dose of each will be used. Thus, forexample, when a compound of the present invention is combined withanother agent, the weight ratio of a disclosed compound to the otheragent will generally range from about 1000:1 to about 1:1000, preferablyabout 200:1 to about 1:200. Combinations of a compound of the presentinvention and other active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

In such combinations a disclosed compound and other active agents can beadministered separately or in conjunction. In addition, theadministration of one element can be prior to, concurrent to, orsubsequent to the administration of other agent(s).

Accordingly, the disclosed compounds can be used alone or in combinationwith other agents which are known to be beneficial in the subjectindications or other drugs that affect receptors or enzymes that eitherincrease the efficacy, safety, convenience, or reduce unwanted sideeffects or toxicity of the disclosed compounds. The subject compound andthe other agent can be coadministered, either in concomitant therapy orin a fixed combination.

In some embodiments, the compound can be employed in combination withany other agent that is used to treat a disorder described herein, suchas a standard of care therapy for a disorder that would benefit frommAChR M₄ antagonism, such as a disorder described herein. For example,in some embodiments, the compound can be employed in combination with aParkinsonian drug (e.g., L-DOPA, or carbidopa/levodopa) an mGlu₄positive allosteric modulator, an mGlu₅ negative allosteric modulator,an A₂A inhibitor, a T-type calcium channel antagonist, a VMAT2inhibitor, a muscle relaxant (e.g., baclofen), an anticholinergic agent,an antiemetic, a typical or atypical neuroleptic agent (e.g.,risperidone, ziprasidone, haloperidol, pimozide, fluphenazine), anantihypertensive agent (e.g., clonidine or guanfacine), a tricyclicantidepressant (e.g., amitriptyline, butriptyline, clomipramine,desipramine, dosulepin, doxepin, imipramine, iprindole, lofepramine,nortriptyline, protriptyline, or trimipramine) an agent that increasesextracellular dopamine levels (e.g., amphetamine, methylphenidate, orlisdexamfetamine), an agent for treating excessive daytime sleepiness(e.g., sodium oxybate or a wakefulness-promoting agent such asarmodafinil or modafinil), and a norepinephrine reuptake inhibitor(including selective NRIs, e.g., atomoxetine, and non-selective NRIs,e.g., bupropion).

-   -   e. Modes of Administration

Methods of treatment may include any number of modes of administering adisclosed composition. Modes of administration may include tablets,pills, dragees, hard and soft gel capsules, granules, pellets, aqueous,lipid, oily or other solutions, emulsions such as oil-in-wateremulsions, liposomes, aqueous or oily suspensions, syrups, elixirs,solid emulsions, solid dispersions or dispersible powders. For thepreparation of pharmaceutical compositions for oral administration, theagent may be admixed with commonly known and used adjuvants andexcipients such as for example, gum arabic, talcum, starch, sugars (suchas, e.g., mannitose, methyl cellulose, lactose), gelatin, surface-activeagents, magnesium stearate, aqueous or non-aqueous solvents, paraffinderivatives, cross-linking agents, dispersants, emulsifiers, lubricants,conserving agents, flavoring agents (e.g., ethereal oils), solubilityenhancers (e.g., benzyl benzoate or benzyl alcohol) or bioavailabilityenhancers e.g. Gelucire™). In the pharmaceutical composition, the agentmay also be dispersed in a microparticle, e.g. a nanoparticulatecomposition.

For parenteral administration, the agent can be dissolved or suspendedin a physiologically acceptable diluent, such as, e.g., water, buffer,oils with or without solubilizers, surface-active agents, dispersants oremulsifiers. As oils for example and without limitation, olive oil,peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil maybe used. More generally spoken, for parenteral administration, the agentcan be in the form of an aqueous, lipid, oily or other kind of solutionor suspension or even administered in the form of liposomes ornano-suspensions.

The term “parenterally,” as used herein, refers to modes ofadministration which include intravenous, intramuscular,intraperitoneal, intrasternal, subcutaneous and intraarticular injectionand infusion.

5 Kits

In one aspect, the disclosure provides a kit comprising at least onedisclosed compound or a pharmaceutically acceptable salt thereof, or apharmaceutical composition comprising at least one disclosed compound ora pharmaceutically acceptable salt thereof and one or more of:

-   -   (a) at least one agent known to increase mAChR M₄ activity;    -   (b) at least one agent known to decrease mAChR M₄ activity_(;)    -   (c) at least one agent known to treat a disorder associated with        mAChR M_(4,) such as a disorder described herein; and    -   (d) instructions for administering the compound.

In some embodiments, the at least one disclosed compound and the atleast one agent are co-formulated. In some embodiments, the at least onedisclosed compound and the at least one agent are co-packaged. The kitscan also comprise compounds and/or products co-packaged, co-formulated,and/or co-delivered with other components. For example, a drugmanufacturer, a drug reseller, a physician, a compounding shop, or apharmacist can provide a kit comprising a disclosed compound and/orproduct and another component for delivery to a patient.

That the disclosed kits can be employed in connection with disclosedmethods of use.

The kits may further comprise information, instructions, or both thatuse of the kit will provide treatment for medical conditions in mammals(particularly humans). The information and instructions may be in theform of words, pictures, or both, and the like. In addition or in thealternative, the kit may include the compound, a composition, or both;and information, instructions, or both, regarding methods of applicationof compound, or of composition, preferably with the benefit of treatingor preventing medical conditions in mammals (e.g., humans).

The compounds and processes of the invention will be better understoodby reference to the following examples, which are intended as anillustration of and not a limitation upon the scope of the invention.

6. Examples

All NMR spectra were recorded on a 400 MHz AMX Bruker NMR spectrometer.¹H chemical shifts are reported in 6 values in ppm downfield with thedeuterated solvent as the internal standard. Data are reported asfollows: chemical shift, multiplicity (s=singlet, bs=broad singlet,d=doublet, t=triplet, q=quartet, dd=doublet of doublets, m=multiplet,ABq=AB quartet), coupling constant, integration. Reversed-phase LCMSanalysis was performed using an Agilent 1200 system comprised of abinary pump with degasser, high-performance autosampler, thermostattedcolumn compartment, C18 column, diode-array detector (DAD) and anAgilent 6150 MSD with the following parameters. The gradient conditionswere 5% to 95% acetonitrile with the aqueous phase 0.1% TFA in waterover 1.4 minutes. Samples were separated on a Waters Acquity UPLC BEHC18 column (1.7 μm, 1.0×50 mm) at 0.5 ml/min, with column and solventtemperatures maintained at 55° C. The DAD was set to scan from 190 to300 nm, and the signals used were 220 nm and 254 nm (both with a bandwidth of 4 nm). The MS detector was configured with an electrosprayionization source, and the low-resolution mass spectra were acquired byscanning from 140 to 700 AMU with a step size of 0.2 AMU at 0.13cycles/second, and peak width of 0.008 minutes. The drying gas flow wasset to 13 liters per minute at 300° C. and the nebulizer pressure wasset to 30 psi. The capillary needle voltage was set at 3000 V, and thefragmentor voltage was set at 100V. Data acquisition was performed withAgilent Chemstation and Analytical Studio Reviewer software.

Abbreviations used in the examples and reaction schemes that follow are:DCM is dichloromethane; DIEA is N,N-diisopropylethylamine; DMF isN,N-dimethylformamide; DMSO is dimethyl sulfoxide; EtOAc is ethylacetate; HATU is1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate; IPA is isopropanol; LAH is lithium aluminumhydride; MeOH is methanol; RuPhos-Pd-G3 ismethanesulfonato(2-dicyclohexyphosphino-2′,6′-di-i-propoxy-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II)(CAS No. 1445085-77-7); STAB is sodium triacetoxyborohydride; and TFA istrifluoroacetic acid.

Example 1.5-(Adamantan-1-ylmethyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5-y)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole(Compound 1)

Tert-butyl1-(6-chloropyridazin-3-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (A). In a microwave vial was added a solution of tort-butylhexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate (600 mg, 2.83 mmol) andN,N-diisopropylethylamine (1.48 mL, 8.48 mmol) in 1-butanol (6.7 mL).Next, 3,6-dichloropyridazine (2105 mg, 14.13 mmol) was added and thevial was sealed. The mixture was heated to 140° C. in a microwavereactor for 1 hr. After LCMS analysis, to the reaction mixture was addeda saturated aqueous NaHCO₃ solution and the aqueous layer was extractedwith CHCl₃/IPA (4:1). The organic layers were pooled and then passedthrough a phase separator and concentrated. Crude product was purifiedusing Teledyne ISCO Combi-Flash system (liquid loading with DCM, 24Gcolumn, 25% EtOAc/Hexanes for 6 minutes, then 0-10% EtOAc/DCM for 10min). Fractions containing product were concentrated to yield the titlecompound A (797 mg, 2.46 mmol, 87% yield) as an off white solid.[M+H]=325.2; RT=0663. ¹H NMR (400 MHz. chloroform-d): δ 7.20-7.22 (d,J=9.5 Hz, 1H), 6.62-6.64 (d, J=9.5 Hz, 1H), 4.51-4.60 (m, 1H), 3.75-3.80 (m, 1H), 3.61-3.66 (m, 2H), 3.43 3.51 (m, 2H), 3.33 3.36 (m, 1H),3.00-3.05 (m, 1H) 2.16-2.24 (m, 1.H), 1.94-2.02 (m, 1H), 1.42 (s, 9H).

Tert-butyl1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)hexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxylate(B). To a microwave vial was added 1,4-dimethylpyrazole-5-boronic acidpinacol ester (105 mg, 0.48mmol), compound A (110 mg, 0.34 mmol),potassium carbonate (143 mg, 1.02 mmol), and RuPhos-Pd-G3 (14 mg, 0.02mmol). The vial was purged with nitrogen and 1,4-dioxane/H₂O (5:1;degassed) was added under an inert atmosphere. The resulting mixture wasstirred at 100° C. for 18 hours, after which time LCMS indicated productformation. The reaction mixture was filtered over Celite, the Celiteplug was washed with DCM, and saturated aqueous NaHCO₃ was added to thefiltrate. The DCM layer was then isolated and the aqueous layer wasextracted with CHCl₃/IPA (4:1) (3×10 mL). The combined organic layerswere passed through a phase separator and concentrated. Crude productwas purified using Teledyne ISCO Combi-Flash system (liquid loading withDCM, 24 G column, 0-50% EtOAc/DCM, 14 min run, then 0-4.5% MeOH/DCM, 19min run) to give the title compound B (120 mg, 0.31 mmol, 92% yield) asan orange oil. [M+H]=385.2; RT=0.673. ¹H NMR (400 MHz, chloroform-d): δ7.35 (s, 1H), 7.31-7.33 (d, J=9.10 Hz, 1H), 6.71-6.73 (d, J=9.10 Hz,1H), 4.59-4.68 (m, 1H), 3.99 (s, 3H) 3.49-3.83 (m, 5H), 3.33-3.34 (m,1H′ 3.06 (s, 1H), 2.18-2.20 (m, 1H), 2.09 (s, 3H), 2.00 (bs, 1H), 1.41(s, 9H).

1-(6-(1,4-Dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole(C). To a vial was added tert-butyl1-[6-(2,4-dimethylpyrazol-3-yl)pyridazin-3-yl]-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrole-5-carboxylate(120 mg, 0.31 mmol) in DCM (1.6 mL) and a solution of 4M HCl in dioxanes(0.39 mL. 1.56 mmol) was added. The mixture was allowed to stir for 18hours. Upon completion, as determined by LCMS, the mixture wasconcentrate to yield the title compound C as the hydrochloride salt (98mg, 0.31 mmol, 97%), as a yellow solid. Product was taken on withoutfurther purification. [M+H]=285.5; RT 0.232.

5-((3r,5r,7r-Adamantan-1-ylmethyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)octanydropyrrolo[3,4-b]pyrrole(Compound 1). To a vial containing a magnetic stir bar was added1-adamantane carboxaldehyde (10.2 mg, 0.060 mmol) and Compound C (as thehydrochloride salt) (10 mg, 0.030 mmol), which were dissolved in DCM (1mL) and acetic acid (0.050 mL). Next, sodium triacetoxyborohydride (16.5mg, 0.080 mmol) was added and the reaction mixture was allowed to stirfor 20 hr. Upon completion (as determined by LC-MS), solvent wasevaporated and the residue was re-dissolved in 1 mL of DMSO. Thecompound was purified on a Gilson preparative reversed-phase HPLC system[Gradient conditions: Hold at 15% CH₃CN in H₂O (0.05% v/v TFA) for 0.75min, 15% to 50% CH₃CN in H₂O (0.05% v/v TFA) over 4 min, hold at 95%CH₃CN in H₂O (0.05% v/v TFA) for 1 min, 50 mL/min, 23° C.]. Fractionscontaining pure product were concentrated, dissolved in CHCl₃/IPA (4:1),and washed with a saturated aqueous solution of NaHCO₃. The organiclayer was passed through a phase separator and concentrated to affordthe title compound (1 mg, 0.002 mmol, 5% yield). [M+H]=433.4; RT=0.720.¹H NMR (400 MHz, chloroform-d): δ 7.38 (s, 1H ), 7.27-7.30 (d, J=9.36Hz, 1H), 6.69-6.72 (d, J=9.36 Hz, 1H), 4.49 (bs, 1H), 4.02 (s, 3H),3.70-3.73 (t, J=6.39 Hz, 2H), 2.91-2.95 (m, 1H), 2.78-2.85 (m, 2H),2.62-2.70 (m, 2H), 2.09-2.22 (m, 2H), 2.11 (s, 3H), 2.05-2.06 (d, 2H),1.99-2.04 (m, 1H), 1.91 (bs, 4H), 1.66-1.73 (m, 4H), 1.58-1.60 (m, 6H).

Example 2.1-(6-(1,4-Dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-(4,4-dimethylpentyl)octahydropyrrolo[3,4-b]pyrrole (Compound 2)

1-(1-(6-(1,4-Dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)hexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)-4,4-dimethylpentan-1-one(D). To a vial containing a magnetic stir bar was added4,4-dimethylpentanoic acid (24.4 mg, 0.19 mmol) and Compound C (as thehydrochloride salt, prepared as described in Example 1) (30 mg, 0.090mmol) dissolved in DMF (1.0 mL). Next, N,N-diisopropylethylamine (0.08mL, 0.47 mmol) and HATU (71.1 mg, 0.19 mmol were added and the reactionmixture was allowed to stir for 18 hr. Upon completion (as determined byLC-MS), solvent was evaporated and the residue was re-dissolved in DMSO(1 mL). Compound was purified on a Gilson preparative reversed-phaseHPLC system [gradient conditions: Hold at 15% CH₃CN in H₂O (0.05% v/vTFA) for 0.75 min, 15% to 50% CH₃CN in H₂O (0.05% v/v TFA) over 10 min,hold at 95% CH₃CN in H₂O (0.05% v/v TFA) for 1 min, 50 mL/min, 23° C].Fractions containing pure product were concentrated, dissolved inCHCl₃IPA (4:1), and washed with a saturated aqueous solution of NaHCO₃.The organic layer was passed through a phase separator and concentratedto afford the title compound D (19.4 mg, 0.049 mmol, 52% yield).[M+H]=397.6; RT=0.679.

1-(6(1,4-Dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-(4,4-dimethylpentyl)octahydropyrrolo[3,4-b]pyrrole(Compound 2). A solution of compound D (14.9 mg, 0.040 mmol) dissolvedin THE (5.7 mL) was cooled to 0° C. where lithium aluminum hydride (37.6μL, 0.040 mmol) was added dropwise. The reaction was allowed to stir for2 hour at 0° C. and then monitored by LCMS. The reaction was slowlyadded to a saturated solution of Rochelle's salt and EtOAc was added(˜10 mL) and the solution was stirred until clear. The organic layer wasremoved and the aqueous layer was further extracted with CHCl₃/IPA (4:1)(3×15 mL). The organic phases were combined, dried over sodium sulfate,filtered, and concentrated. The crude product was dissolved in DMSO (1mL) and purified using the Gilson (Acid, 30×100 mm column, 10-65%ACN/0.1% aqueous TFA, 10 min run). Fractions containing pure productwere concentrated, dissolved in CHCl₃/IPA (4:1), and washed with asaturated aqueous solution of NaHCO_(3.) The organic layer was passedthrough a phase separator and concentrated to afford Compound 2 (2.1mg,0.0055 mmol, 15% yield), [M+H]=383.6; RT=0.641.

Example 3. Additional Compounds

The compounds shown in Table 1 were prepared similarly e compoundsdescribed in Examples 1 and 2, with appropriate starting materials.

TABLE 1 Cpd. ES-MS No. Name Structure [M + 1]⁺  35-(bicyclo[2.2.1]hept-5-en-2- ylmethyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3- yl)octahydropyrrolo[3,4-b]pyrrole

391.3  4 1-(6-(1,4-dimethyl-1H-pyrazol-5- yl)pyridazin-3-yl)-5-((3-methylpyridin-2- yl)methyl)octahydropyrrolo[3,4- b]pyrrole

390.2  5 5-benzyl-1-(6-(1,4-dimethyl-1H- pyrazol-5-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole

375.2  6 1-(6-(1,4-ditnethyl-1H-pyrazol-5- yl)pyridazin-3-yl)-5-phenethyloctahydropyrrolo[3,4- b]pyrrole

389.2  7 1-(6-(1,4-dimethyl-1H-pyrazol-5- yl)pyridazin-3-yl)-5-(3-phenylpropyl)octahydropyrrolo[3,4- b]pyrrole

403.2  8 5-((1-benzylpiperidin-4-yl)methyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5- yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole

472.5  9 1-(6-(1,4-dimethyl-1H-pyrazol-5- yl)pyridazin-3-yl)-5-(3-phenylbutyl)octahydropyrrolo[3,4- b]pyrrole

417.5 10 5-(adamantan-2-ylmethyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin- 3-yl)octahydropyrrolo[3,4-b]pyrrole

433.5 11 1-(6-(1,4-dimethyl-1H-pyrazol-5- yl)pyridazin-3-yl)-5-(2-phenylpropyl)octahydropyrrolo[3,4- b]pyrrole

403.5 12 (Z)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-(hept-4-en-1- yl)octahydropyrrolo[3,4-b]pyrrole

381.6 13 1-(6-(1,4-dimethyl-1H-pyrazol-5- yl)pyridazin-3-yl)-5-hexyloctahydropyrrolo[3,4-b]pyrrole

369.5 14 1-(6-(1,4-dimethyl-1H-pyrazol-5- yl)pyridazin-3-yl)-5-(2,2-diphenylethyl)octahydropyrrolo[3,4- b]pyrrole

465.4 15 5-(adamantan-1-ylmethyl)-1-(6-(4-ethylpyridin-3-yl)pyridazin-3- yl)octahydropyrrolo[3,4-b]pyrrole

444.4 16 5-(adamantan-1-ylmethyl)-1-(6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridazin- 3-yl)octahydropyrrolo[3,4-b]pyrrole

433.4 17 5-(adamantan-1-ylmethyl)-1-(6-(2-chloro-5-fluorophenyl)pyridazin-3- yl)octahydropyrrolo[3,4-b]pyrrole

467.2 18 5-(adamantan-1-ylmethyl)-1-(6-(2-chloro-4-fluorophenyl)pyridazin-3- yl)octahydropyrrolo[3,4-b]pyrrole

467.2 19 5-(adamantan-1-ylmethyl)-1-(6- (1,3,5-trimethyl-1H-pyrazol-4-yl)pyridazin-3- yl)octahydropyrrolo[3,4-b]pyrrole

447.6 20 1-(6-(1,4-dimethyl-1H-pyrazol-5- yl)pyridazin-3-yl)-5-(3,3-dimethylbutyl)octahydropyrrolo[3,4- b]pyrrole

369.5 21 (3aR,6aR)-5-(adamantan-1- ylmethyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3- yl)octahydropyrrolo[3,4-b]pyrrole

433.5 22 1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-((tetrahydro- 2H-pyran-4-yl)methyl)octahydropyrrolo[3,4- b]pyrrole

383.5 23 (3aS,6aS)-5-(adamantan-1- ylmethyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3- yl)octahydropyrrolo[3,4-b]pyrrole

433.5

Example 4. Biological Activity

-   -   A. Cell Lines Expressing Muscarinic Acetylcholine Receptors

Human or rat M₄ cDNA, along with the chimeric G protein G_(qi5), weretransfected into Chinese hamster ovary (CHO-Kl) cells purchased from theAmerican Type Culture Collection using Lipofectamine2000. M₄/G_(qi5)/CHOcells were grown in Ham's F-12 medium containing 10% heat-inactivatedfetal bovine serum (FBS), 20 mM HEPES, 500 μg/mL G418 sulfate, and 200μg/mL Hygromycin B.

-   -   B. Cell-Based Functional Assay of Muscarinic Acetylcholine        Receptor Activity

For high throughput measurement of agonist-evoked increases inintracellular calcium, CHO-Kl cells stably expressing muscarinicreceptors were plated in growth medium lacking G418 and hygromycin at15,000 cells/20 μL/well in Greiner 384-well black-walled, tissue culture(TC)-treated, clear-bottom plates (VWR). Cells were incubated overnightat 37° C. and 5% CO₂. The next day, cells were washed using an ELX 405(BioTek) with assay buffer; the final volume was then aspirated to 20Next, 20 μL of a 2.3 μM stock of Fluo-4/acetoxymethyl ester (Invitrogen,Carlsbad, Calif.), prepared as a 2.3 mM stock in DMSO and mixed in a 1:1ratio with 10% (w/v) Pluronic F-127 and diluted in assay buffer, wasadded to the wells and the cell plates were incubated for 50 min at 37°C. and 5% CO₂. Dye was removed by washing with the ELX 405 and the finalvolume was aspirated to 20 μL. Compound master plates were formatted ina 10 point concentration-response curve (CRC) format (1:3 dilutions) in100% DMS( )with a starting concentration of 10 or 1 mM using a BRAVOliquid handler (Agilent). Test compound CRCs were then transferred todaughter plates (240 nL) using the Echo acoustic plate reformatter(Labcyte, Sunnyvale, Calif.) and then diluted into assay buffer (40 μL)to a 2× stock using a Thermo Fisher Combi (Thermo Fisher Scientific,Waltham, Mass.).

Calcium flux was measured using the Functional Drug Screening System(FDSS) 6000 or 7000 (Hamamatsu Corporation, Tokyo, Japan) as an increasein the fluorescent static ratio. Compounds were applied to cells (20 μL,2×) using the automated system of the FDSS at 2 seconds into theprotocol and the data were collected at 1 Hz. At 143 s, 10 μL of an EC₂₀concentration of the muscarinic receptor agonist acetylcholine was added(5×), followed by the addition of 12 μL of an EC₂₀ concentration ofacetylcholine at the 268 s time point (5×). Agonist activity wasanalyzed as a concentration-dependent increase in calcium mobilizationupon compound addition. Positive allosteric modulator activity wasanalyzed as a concentration-dependent increase in the EC₂₀ acetylcholineresponse. Antagonist activity was analyzed as a concentration-dependentdecrease in the EC₈₀ acetylcholine response for the purposes of thetables herein, an IC₅₀ (inhibitory concentration 50) was calculated as aconcentration-dependent decrease of the response elicited by an EC₈₀concentration of acetylcholine, Concentration-response curves weregenerated using a four-parameter logistical equation in XLFit curvefitting software (IDBS, Bridgewater, N.J.) for Excel (Microsoft,Redmond, Wash.) or Prism (GraphPad Software, Inc., San Diego, Calif.) orthe Dotrnatics software platform (Dotmatics, Bishop's Stortford, UK).

The above described assay was also operated in a second mode where anappropriate fixed concentration of the present compounds were added tothe cells after establishment of a fluorescence baseline for about 3seconds, and the response in cells was measured. 140 s later, a fullconcentration-response range consisting of increasing concentrations ofagonist was added and the calcium response (maximum-local minimaresponse) was measured. The EC₅₀ values for the agonist in the presenceor absence of test compound were determined by nonlinear curve fitting.A decrease in the EC₅₀ value of the agonist with increasingconcentrations of the present compounds (a leftward shift of the agonistconcentration-response curve) an indication of the degree of muscarinicpositive allosteric modulation at a given concentration of the presentcompound. An increase in the EC₅₀ value of the agonist with increasingconcentrations of the present compounds (a rightward shift of theagonist concentration response curve) is an indication of the degree ofmuscarinic antagonism at a given concentration of the present compound.The second mode also indicates whether the present compounds also affectthe maximum response of the muscarinic receptor to agonists.

-   -   C. Activity of Compounds in a mAChR M₄ Cell-Based Assay

Compounds were synthesized as described above. Activity (IC₅₀ andE_(min)) was determined in the mAChR M₄ cell-based functional assay asdescribed above and the data are shown in Table 2. The compound numbercorresponds to the compound numbers used in Examples 1-3.

TABLE 2 Cpd. Rat M₄ E_(min) Human M₄ E_(min) No. IC₅₀ (μM) (%)* IC₅₀(μM) (%)* 1 0.509 4.61 ND ND 2 1.50  6.85 0.647 3.83 3 3.57  16.79 0.8004.28 4 >10 μM 63.13 >10 μM 26.25 5 ND ND >10 μM 46.7 6 >10 μM 30.941.98  7.19 7 >10 μM 26.19 1.43  6.12 8 >10 μM 32.43 3.38  6.61 9 2.33 6.32 0.498 4.33 10 1.89  4.82 0.453 4.12 11 >10 μM 55.48 >10 μM 15.1112 >10 μM 45.19 >10 μM 15.07 13 >10 μM 28.37 2.15  7.23 14 >10 μM 48.349.19  8.96 15 1.71  3.98 0.899 4.18 16 0.753 4.09 0.191 4.02 17 >10 μM49.07 >10 μM 20.25 18 >10 μM 36.39 >10 μM 12 19 0.365 4.41 0.129 3.1820 >10 μM 22.73 2.22  8.8 21 0.601 3.71 0.147 4.08 22 >10 μM 69.68 >10μM 36.07 23 0.326 4.52 0.102 3.91 *% ACh maximum at 30 μM. ND = notdetermined

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents.

Various changes and modifications to the disclosed embodiments will beapparent to those skilled in the art. Such changes and modifications,including without limitation those relating to the chemical structures,substituents, derivatives, intermediates, syntheses, compositions,formulations, or methods of use of the invention, may be made withoutdeparting from the spirit and scope thereof.

What is claimed is:
 1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: A is a five- orsix-membered heteroarylene having 1, 2 or 3 heteroatoms independentlyselected from N, O and S; R¹ is selected from hydrogen, halo, —OR^(a),—NR^(b)R^(c), aryl, and heteroaryl; R² is selected from hydrogen, C₁-C₄alkyl, halo, and —OR^(d); R³ is selected from hydrogen and C₁-C₄ alkyl;R⁴ is selected from C₁-C₈ alkyl, C₁-C₈ alkenyl, and—(CR^(e)R^(f))_(n)—Y′; each Y′ is independently selected fromcycloalkyl, cycloalkenyl, heterocycle, aryl, and heteroaryl; each R^(a),R^(b), R^(c), and R^(d) is independently selected from hydrogen, C₁-C₄alkyl, C₃-C₆ cycloalkyl, and aryl; each R^(e) is independently selectedfrom hydrogen and C₁-C₄ alkyl; each R^(f) is independently selected fromhydrogen, C₁-C₄ alkyl, and aryl; and n is 0, 1, 2, 3, or 4; wherein eacharyl, heteroaryl, cycloalkyl, cycloalkenyl, and heterocycle isindependently unsubstituted or substituted with 1, 2, or 3 substituentsindependently selected from C₁-C₄ alkyl, halo, C₁-C₄ haloalkyl, C₁-C₄alkoxy, C₁-C₄ haloalkoxy, C₁-C₄ hydroxyalkyl, hydroxy, cyano, andbenzyl.
 2. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein A is selected from:

wherein: T is selected from O, S and NH; U, V, W, V, X, Y and Z areindependently selected from N and CR^(g.), and each R^(g) isindependently selected from hydrogen, C₁-C₄ alkyl, halo, C₁-C₄haloalkyl, C₁-C₄ alkoxy, haloalkoxy, and hydroxy, wherein 1-3 of W, X,Y, and Z are N.
 3. The compound of claim 2, or a pharmaceuticallyacceptable salt thereof, wherein A is selected from:


4. The compound of any one of claims 1-3, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is selected from aryl andheteroaryl, wherein the aryl and heteroaryl are unsubstituted orsubstituted with 1, 2, or 3 substituents independently selected fromC₁-C₄ alkyl, halo, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkoxy,C₁-C₄ hydroxyalkyl, hydroxy, cyano, and benzyl. The compound of claim 4,or a pharmaceutically acceptable salt thereof, wherein R¹ is selectedfrom phenyl and a 5- or 6-membered heteroaryl having 1, 2, or 3heteroatoms independently selected from N, O, and S; and the phenyl orheteroaryl is unsubstituted or substituted with 1, 2, or 3 substituentsindependently selected from halo and C₁-C₄ alkyl.
 6. The compound of anyone of claims 1-5, or a pharmaceutically acceptable salt thereof,wherein R² is hydrogen.
 7. The compound of any one of claims 1-6, or apharmaceutically acceptable salt thereof, wherein R² is hydrogen.
 8. Thecompound of any one of claims 1-7, or a pharmaceutically acceptable saltthereof, wherein R⁴ is selected from C₄-C₆ alkyl and C₄-C₆ alkenyl. 9.The compound of any one of claims 1-7, or a pharmaceutically acceptablesalt thereof, wherein R⁴ is —(CR^(e)R^(f))_(n)—Y′; R^(e) is hydrogen;each R^(f) is independently selected from hydrogen, methyl, and phenyl;n is 0, 1, 2, or 3; Y′ is selected from: C₃-C₁₀ cycloalkyl; C₅-C₁₀cycloalkenyl; phenyl; a 5- or 6-membered heteroaryl having 1, 2, or 3heteroatoms independently selected from N, O, and S; and a 5- or6-membered heterocycle having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S; wherein Y′ is unsubstituted or substitutedwith one or two substituents independently selected from halo, C₁-C₄alkyl, and benzyl.
 10. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein the compound is a compound of formula(Ia):


11. The compound of claim 10, or a pharmaceutically acceptable saltthereof, wherein R¹ is selected from aryl and heteroaryl.
 12. Thecompound of claim 11, or a pharmaceutically acceptable salt thereof,wherein R¹ is selected from phenyl and a 5- or 6-membered heteroarylhaving 1, 2, or 3 heteroatoms independently selected from N, O, and S;and the phenyl or heteroaryl is unsubstituted or substituted with 1, 2,or 3 substituents independently selected from halo and C₁-C₄ alkyl. 13.The compound of any one of claims 10-12, or a pharmaceuticallyacceptable salt thereof, wherein R³ is hydrogen; R⁴ is—(CR^(e)R^(f))_(n)—Y′; R^(e) is hydrogen; each R^(f) is independentlyselected from hydrogen, methyl, and phenyl; n is 0, 1, 2, or 3; Y′ isselected from: C₃-C₁₀ cycloalkyl; C₅-C₁₀ cycloalkenyl; phenyl; a 5- or6-membered heteroaryl having 1, 2, or 3 heteroatoms independentlyselected from N, O, and S; and a 5- or 6-membered heterocycle having 1,2, or 3 heteroatoms independently selected from N, O, and S; wherein Y′is unsubstituted or substituted with one or two substituentsindependently selected from halo, C₁-C₄alkyl, and benzyl.
 14. Thecompound of claim 1, wherein the compound is selected from the groupconsisting of:5-(adamantan-1-ylmethyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole;1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-(4,4-dimethylpentyl)octahydropyrrolo[3,4-b]pyrrole;5-(bicyclo[2.2.1]hept-5-en-2-ylmethyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole;1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-((3-methylpyridin-2-yl)methyl)octahydropyrrolo[3,4-b]pyrrole;5-benzyl-1-(6(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole;1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-phenethyloctahydropyrrolo[3,4-b]pyrrole;1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-(3-phenylpropyl)octahydropyrrolo[3,4-b]pyrrole;5-((1-benzylpiperidin-4-yl)methyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole;1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-(3-phenylbutyl)octahydropyrrolo[3,4-b]pyrrole;5-(adamantan-2-ylmethyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole;1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-(2-phenylpropyl)octahydropyrrolo[3,4-b]pyrrole;(Z)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-(hept-4-en-1-yl)octahydropyrrolo[3,4-b]pyrrole;1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-hexyloctahydropyrrolo[3,4-b]pyrrole;1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-(2,2-diphenylethyl)octahydropyrrolo[3,4-b]pyrrole;5-(adamantan-1-ylmethyl)-1-(6-(4-ethylpyridin-3-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole;and5-(adamantan-1-ylmethyl)-1-(6-(1,3-dimethyl-1H-pyrazol-4-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole,5-(adamantan-1-ylmethyl)-1-(6-(2-chloro-5-fluorophenyl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole;5-(adamantan-1-ylmethyl)-1-(6-(2-chloro-4-fluorophenyl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole;5-(adamantan-1-ylmethyl)-1-(6-(1,3,5-trimethyl-1H-pyrazol-4-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole;1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-(3,3-dimethylbutyl)octahydropyrrolo[3,4-b]pyrrole;(3aR,6aR)-5-(adamantan-1-ylmethyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole;1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)-5-((tetrahydro-2-pyran-4-yl)methyl)octahydropyrrolo[3,4-b]pyrrole;and(3aS,6aS)-5-(adamantan-1-ylmethyl)-1-(6-(1,4-dimethyl-1H-pyrazol-5-yl)pyridazin-3-yl)octahydropyrrolo[3,4-b]pyrrole,or a pharmaceutically acceptable salt thereof.
 15. The compound of anyone of claims 1-14, or a pharmaceutically acceptable salt thereof,wherein the compound is isotopically labeled.
 16. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof any one of claims 1-15, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.
 17. A method forantagonizing mAChR. M₄ in a subject, comprising a step of administeringto the subject a therapeutically effective amount a compound of any oneof claims 1-15, or a pharmaceutically acceptable salt thereof, or thepharmaceutical composition of claim
 16. 18. A method for treating adisorder in a subject, wherein the subject would benefit from antagonismof mAChR M_(4,) comprising a step of administering to the mammal atherapeutically effective amount a compound of any one of claims 1-15,or a pharmaceutically acceptable salt thereof, or the pharmaceuticalcomposition of claim
 16. 19. The method of claim 18, wherein thedisorder is a movement disorder.
 20. The method of claim 19, wherein thedisorder is selected from Parkinson's disease, drug-inducedParkinsonism, dystonia, Tourette's syndrome, dyskinesias, schizophrenia,cognitive deficits associated with schizophrenia, excessive daytimesleepiness, attention deficit hyperactivity disorder (ADHD),Huntington's disease, chorea, cerebral palsy, and progressivesupranuclear palsy.
 21. A method for treating motor symptoms in asubject, comprising administering to a subject in need thereof atherapeutically effective amount of the compound of any one of claims1-15, or a pharmaceutically acceptable salt thereof, or thepharmaceutical composition of claim
 16. 22. The method of claim 21,wherein the subject has a disorder selected from Parkinson's disease,drug-induced Parkinsonism, dystonia, Tourette's syndrome, dyskinesias,schizophrenia, cognitive deficits associated with schizophrenia,excessive daytime sleepiness, attention deficit hyperactivity disorder(ADHD), Huntington's disease, chorea, cerebral palsy, and progressivesupranuclear palsy.
 23. A compound of any of claims 1-15, or apharmaceutically acceptable salt thereof, or the pharmaceuticalcomposition of claim 16, for use in the treatment of a movementdisorder.
 24. Use of the compound of any of claims 1-15, or apharmaceutically acceptable salt thereof, or the pharmaceuticalcomposition of claim 16, for the preparation of a medicament for thetreatment of a movement disorder.